Methods for treating neuroblastoma

ABSTRACT

Methods of treating neuroblastoma associated with a deregulated protein kinase activity are disclosed. The treatment may include administration of substituted indazole derivatives of formula (I) or formula 2.(I) and pharmaceutically acceptable salts therefor, as degined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/114,367, filed Jul. 26, 2016; which is a National Stage Entry of PCTInternational Application No. PCT/EP2015/053544, filed Feb. 19, 2015,which claims the benefit of U.S. Provisional Application No. 61/942,287,filed on Feb. 20, 2014; 62/052,994, filed on Sep. 19, 2014; 62/055,450,filed on Sep. 25, 2014; and 62/069,999, filed on Oct. 29, 2014; each ofwhich is incorporated herein by reference in its entirety; including anydrawings.

PARTIES OF JOINT RESEARCH AGREEMENT

The compositions and methods disclosed herein are subject to a jointresearch agreement between Ignyta, Inc. and Nerviano Medical Sciencess.r.l., executed Oct. 10, 2013.

FIELD OF THE INVENTION

The present invention relates to certain substituted indazole compounds,which modulate the activity of protein kinases. The compounds of thisinvention are therefore useful in treating diseases caused byderegulated protein kinase activity. The present invention also providesmethods for preparing these compounds, pharmaceutical compositionscomprising these compounds, and methods of treating diseases utilizingpharmaceutical compositions comprising these compounds.

BACKGROUND OF THE INVENTION

The malfunctioning of protein kinases (PKs) is the hallmark of numerousdiseases. A large share of the oncogenes and proto-oncogenes involved inhuman cancers encode for PKs. The enhanced activities of PKs are alsoimplicated in many non-malignant diseases, such as benign prostatehyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis andpost-surgical stenosis and restenosis.

PKs are also implicated in inflammatory conditions and in themultiplication of viruses and parasites. PKs may also play a major rolein the pathogenesis and development of neurodegenerative disorders.

For a general reference to PKs malfunctioning or deregulation see, forinstance, Current Opinion in Chemical Biology 1999, 3:459-465.

A subset of PK is a group of membrane receptors with intrinsicprotein-tyrosine kinase activity (RPTK). Upon binding of grow factors,RPTKs become activated and phosphorylate themselves and a series ofsubstrates in the cytoplasm. Through this mechanism, they can transduceintracellular signalings for proliferation, differentiation or otherbiological changes. Structural abnormalities, over-expression andactivation of RTPKs are frequently observed in human tumors, suggestingthat constitutive ignition of the signal transduction leading to cellproliferation can result in malignant transformation. Anaplasticlymphoma kinase (ALK) is a tyrosine kinase receptor belonging to theinsulin receptor subfamily of RTKs: the ALK gene is located onchromosome 2 and is expressed mainly in neuronal cells, especiallyduring development. The ALK gene is involved in a balanced chromosomaltranslocation with the Nucleophosmin (NPM) gene on chromosome 5 in alarge subset of Anaplastic Large Cell Lymphomas (ALCL). In the ALK+ALCL, as a result of the translocation, the NPM ubiquitous promoterdrives an ectopic expression of the fusion protein in which the NPMmoiety dimerizes and the ALK kinase domain undergoesauto-phosphorylation and becomes constitutively active.

Many data from the literature have demonstrated that the NPM-ALK fusionprotein has a strong oncogenic potential and its ectopic expression isresponsible for cellular transformation. Moreover, the constitutiveexpression of human NPM-ALK in mouse T-cell lymphocytes is sufficientfor the development of lymphoid neoplasia in transgenic animals with ashort period of latency.

ALCL is a defined disease characterized by the surface expression of theCD30 antigen (Ki-1), and accounts for 2% of adult and 13% of pediatricnon-Hodgkin's lymphomas, affecting predominantly young male patients.ALK+ ALCL accounts for 70% of all ALCLs and is an aggressive diseasewith systemic signs, and frequent extranodal involvement (bone marrow,skin, bone, soft tissues).

About 15-20% of ALK-expressing ALCLs were found to bear a differentchromosomal translocation, involving the cytoplasmic portion of ALK,with different N-terminal moieties, all resulting in constitutiveactivation of the ALK kinase domain.

Moreover, cell lines established from solid tumors of ectodermal originlike melanomas, breast carcinomas, as well as neuroblastomas,glioblastomas, Ewings sarcomas, retinoblastomas, were found to expressthe ALK receptor.

ROS1 belongs to the insulin-receptor superfamily. Like other tyrosinekinase receptor molecules, it plays a role in relaying growth signalsfrom the environment outside the cell into the cell's nucleus. It is 1of 2 orphan receptor tyrosine kinase family members with no knownbinding ligand. Genetic changes in ROS1, such as gene rearrangements,mutations, or copy number increases, create oncogenes, which can lead tocancer (Stumpfova and Janne, 2012). ROS1 was discovered in NSCLCpatients in the form of a fusion protein (6 different partners for ROS1)and is found in approximately 2% of patients with NSCLC (Bergethon etal., 2012; Davies et al, 2012). Two other ROS1 gene rearrangements havebeen detected in a variety of other cancers, including glioblastomamultiforme, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma,colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, andepitheloid hemangioendothelioma (Lee et al., 2013; Davies and Doebele,2013; Davies, et al., 2012; Shaw et al., 2013).

ROS1 gene rearrangements create fusion proteins with constitutivelyactive kinase domains that activate downstream signaling pathwaysleading to oncogenic properties in cells, including uncontrolledproliferation and resistance to cell death with prolonged tumor cellsurvival. These pathways include Ras-ERK for cellular proliferation andthe JAK-STAT and PI3K/AKT pathways, which regulate cell survival(anti-apoptosis) and proliferation. ROS1 fusion proteins may alsoactivate the mTOR pathway, which is critical for the regulation ofprotein translation. Cancers that have these pathways activated tend tobe more aggressive, with invasion and metastasis leading to poorsurvival of the patients (Davies and Doebele, 2013).

Trk's are the high affinity receptor tyrosine kinases activated by agroup of soluble growth factors called neurotrophins (NT). The Trkreceptor family has three members—TrkA, TrkB and TrkC. Among theneurotrophins are (i) nerve growth factor (NGF) which activates TrkA,(ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activateTrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed inneuronal tissue and are implicated in the maintenance, signaling andsurvival of neuronal cells (Patapoutian, A. et al., Current Opinion inNeurobiology, 2001, 11, 272-280). NTRK1 encodes the TrkA receptortyrosine kinase. TrkA activates the PI3K/AKT, PKC and ERK1/2 pathwayswhich promote cell growth and survival.

Inhibitors of the Trk/neurotrophin pathway have been demonstrated to beeffective in numerous pre-clinical animal models of pain. For example,antagonistic NGF and TrkA antibodies (for example, RN-624) have beenshown to be efficacious in inflammatory and neuropathic pain animalmodels and in human clinical trials (Woolf, C. J. et al. (1994)Neuroscience 62, 327-331; Zahn, P. K. et al. (2004) J. Pain 5, 157-163;McMahon, S. B. et al., (1995) Nat. Med. 1, 774-780; Ma, Q. P. and Woolf,C. J. (1997) Neuroreport 8, 807-810; Shelton, D. L. et al. (2005) Pain116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al.(2003) Neurogastroenterol. Motil. 15, 355-361; Jaggar, S. I. et al.(1999) Br. J. Anaesth. 83, 442-448). Additionally, recent literatureindicates after inflammation, BDNF levels and TrkB signaling isincreased in the dorsal root ganglion (Cho, L. et al. Brain Research1997, 749, 358) and several studies have show antibodies that decreasesignaling through the BDNF/TrkB pathway inhibit neuronalhypersensitization and the associated pain (Chang-Qi, L et al. MolecularPain 2008, 4:27).

In addition, it has been shown that tumor cell sand tumor invadingmacrophages directly stimulates TrkA located on peripheral pain fibers.Using various tumor models in both mice and rats it was demonstratedthat neutralizing NGF with a monoclonal antibody inhibits cancer relatedpain to a degree similar or superior to the highest tolerated dose ofmorphine. In addition, activation of the BDNF/TrkB pathway has beenimplicated in numerous studies as a modulator of various types of painincluding inflammatory pain (Matayoshi, S., J. Physiol. 2005,569:685-95), neuropathic pain (Thompson, S. W., Proc. Natl. Acad. Sci.USA 1999, 96:7714-18) and surgical pain (Li, C.-Q. et al., MolecularPain, 2008, 4(28), 1-11). Because TrkA and TrkB kinases may serve as amediator of NGF driven biological responses, inhibitors of TrkA and/orother Trk kinases may provide an effective treatment for chronic painstates.

Recent literature has also shown that overexpression, activation,amplification and/or mutation of Trk's are associated with many cancersincluding neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003, 3,203-216), ovarian cancer (Davidson. B., et al., Clin. Cancer Res. 2003,9, 2248-2259), breast cancer (Kruettgen et al, Brain Pathology 2006, 16:304-310), prostate cancer (Dionne et al, Clin. Cancer Res. 1998, 4(8):1887-1898), pancreatic cancer (Dang et al, Journal of Gastroenterologyand Hepatology 2006, 21(5): 850-858), multiple myeloma (Hu et al, CancerGenetics and Cytogenetics 2007, 178: 1-10), astrocytoma andmedulloblastoma (Kruettgen et al, Brain Pathology 2006, 16: 304-310)glioma (Hansen et al, Journal of Neurochemistry 2007, 103: 259-275),melanoma (Truzzi et al, Journal of Investigative Dermatology 2008,128(8): 2031-2040, thyroid carcinoma (Brzezianska et al,Neuroendocrinology Letters 2007, 28(3), 221-229.), lung adenocarcinoma(Perez-Pinera et al, Molecular and Cellular Biochemistry 2007, 295(1&2),19-26), large cell neuroendocrine tumors (Marchetti et al, HumanMutation 2008, 29(5), 609-616), and colorectal cancer (Bardelli, A.,Science 2003, 300, 949). In preclinical models of cancer, Trk inhibitorsare efficacious in both inhibiting tumor growth and stopping tumormetastasis. In particular, non-selective small molecule inhibitors ofTrk A, B and C and Trk/Fc chimeras were efficacious in both inhibitingtumor growth and stopping tumor metastasis (Nakagawara, A. (2001) CancerLetters 169:107-114; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia,M. A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens,E. et al. Cancer Res (2008) 68:(2) 346-351) (Truzzi et al, Journal ofInvestigative Dermatology 2008, 128(8): 2031-2040. Therefore, aninhibitor of the Trk family of kinases is expected to have utility inthe treatment of cancer.

Various gene rearrangements of the Trk gene have been implicated inhuman malignancies. For example, the MPRIP-NRTK1 and CD74-NRTK1 generearrangements have been implicated in the development of non-small celllung cancer. Gene rearrangements TPM3-NRTK1, TGF-NTRK1 and TPR-NTRK1have been implicated in the development of papillary thyroid cancer. TheTPM3-NTRK1 gene rearrangement has been implicated in the development ofcolorectal cancer. NTRK1, NTRK2 or NTRK3 gene rearrangements have alsobeen identified in glioblastoma, AML and secretory breast cancer. In2013, Vaishnavi et al. reported novel NTRK1 fusions in 3/91 pan-negativepatients with lung adenocarcinoma using NGS and FISH (Vaishnavi et al.Nat Med. 2013 November: 19(11):1469-72).

In addition, inhibition of the neurotrophin/Trk pathway has been shownto be effective in treatment of pre-clinical models of inflammatorydiseases. For example, inhibition of the neurotrophin/Trk pathway hasbeen implicated in preclinical models of inflammatory lung diseasesincluding asthma (Freund-Michel, V; Frossard, N.; Pharmacology &Therapeutics (2008), 117(1), 52-76), interstitial cystitis (Hu Vivian Y;et. al. The Journal of Urology (2005), 173(3), 1016-21), inflammatorybowel diseases including ulcerative colitis and Crohn's disease (DiMola, F. F, et. al., Gut (2000), 46(5), 670-678) and inflammatory skindiseases such as atopic dermatitis (Dou, Y.-C.; et. al. Archives ofDermatological Research (2006), 298(1), 31-37), eczema and psoriasis(Raychaudhuri, S. P.; et. al. Journal of Investigative Dermatology(2004), 122(3), 812-819).

The neurotrophin/Trk pathway, particularly BDNF/TrkB, has also beenimplicated in the etiology of neurodegenerative diseases includingmultiple sclerosis, Parkinson's disease and Alzheimer's disease(Sohrabji, Farida; Lewis, Danielle K. Frontiers in Neuroendocrinology(2006), 27(4), 404-414). Modulation of the neutrophin/Trk pathway mayhave utility in treatment of these and related diseases.

The TrkA receptor is also thought to be critical to the disease processin the infection of the parasitic infection of Typanosoma cruzi (Chagasdisease) in human hosts (de Melo-Jorge, M. et al. Cell Host & Microbe(2007), 1(4), 251-261). Thus, TrkA inhibition my have utility intreating Chagas disease and related protozoan infections.

Trk inhibitors may also find use in treating disease related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases. Bone metastases are afrequent complication of cancer, occurring in up to 70 percent ofpatients with advanced breast or prostate cancer (1) and inapproximately 15 to 30 percent of patients with carcinoma of the lung,colon, stomach, bladder, uterus, rectum, thyroid, or kidney. Osteolyticmetastases can cause severe pain, pathologic fractures, life-threateninghypercalcemia, spinal cord compression, and other nerve-compressionsyndromes. For these reasons, bone metastasis is a serious and costlycomplication of cancer. Therefore, agents that can induce apoptosis ofproliferating osteoblasts would be highly advantageous. Expression ofTrkA and TrkC receptors has been observed in the bone forming area inmouse models of bone fracture (K. Asaumi, et al., Bone (2000) 26(6)625-633). In addition, localization of NGF was observed in almost allbone forming cells (K. Asaumi, et al.). Recently, it was demonstratedthat a pan-Trk inhibitor inhibits the tyrosine signaling activated byneurotrophins binding to all three of the Trk receptors in human hFOBosteoblasts (J. Pinski, et al., (2002) 62, 986-989). These data supportthe rationale for the use of Trk inhibitors for the treatment of boneremodeling diseases, such as bone metastases in cancer patients.

In conclusion, interfering with ALK or ROS1 signaling likely representsa specific and effective way to block tumor cell proliferation in ALCLand possibly other indications. The insulin-like growth factor 1receptor (IGF-1R, IGF1R) is also a member of the insulin receptorsubfamily of RTKs.

In addition, interfering with TrkA, TrkB and/or TrkC signaling, or acombination thereof, represents a specific and effective way to blocktumor cell proliferation in various cancers, including, but not limitedto, non-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer.

There exist several lines of evidence suggesting that IGF-1R signalingcan contribute to tumorigenesis, and that interfering with IGF-1Rfunction represents a valid therapeutic option in cancer. For anoverview of IGFs and IGF-1R signaling, physiological function, anddetailed description of the evidence supporting involvement of thissystem in human cancer that is summarized above, as well as in otherpathologies, the reader is directed to the many reviews on the subjectand references contained therein, for example Baserga R. et al, BiochimBiophys Acta vol. 1332, pages F105-F126, 1997; Khandwala H. M. et al,Endocr Rev vol. 21, pages 215-44, 2000; Le Roith D. et al, Endocr Revvol. 22, pages 53-74, 2001; Valentinis B. et al, Mol Pathol vol. 54,pages 133-7, 2001; Wang Y. et al, Curr Cancer Drug Targets vol. 2, pages191-207, 2002; Laron, Z. J Clin Endocrinol Metab vol. 89, pages1031-1044, 2004; Hofmann F et al, Drug Discov Today vol. 10, pages1041-7, 2005.

SUMMARY OF THE INVENTION

3-Amino and 3-acylamino indazole derivatives for the treatment ofneurodegenerative diseases, cerebrovascular accidents, obesity,cardiovascular diseases and cancer are disclosed in WO2006003276,WO2004022544 and WO 2003078403 in the name of Aventis Pharma SA.

Indazolyl amide derivatives for the treatment of diabetes,neurodegenerative conditions such as Alzheimer's disease and Parkinson'sdisease are disclosed in WO2003051847 in the name of SmithKline BeechamP.L.C.

Indazole derivatives for the treatment of tumor disease, viral disease,immunosuppression in transplantation, cystic fibrosis and diseasesassociated with angiogenesis are disclosed in WO2008003396 in the nameof Merck GMBH.

Despite these developments, there is still a need for more effectiveagents for the treatment of such diseases.

We have now discovered that a series of indazoles are potent proteinkinase inhibitors and are thus useful in anticancer therapy.

Accordingly, an object of the present invention is to provide asubstituted indazole compound represented by formula (I), or formula2.(I).

More particularly, a first object of the present invention is to providea substituted indazole compound represented by formula (I),

wherein: ●X is —CH2-, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, wherein: ∘R′ isan optionally further substituted straight or branched C1-C6 alkyl andR″ is hydrogen or an optionally further substituted straight or branchedC1-C6 alkyl; ●Ar is aryl or heteroaryl optionally substituted with oneor more substituents independently selected from halogen, C2-C6 alkenyl,C2-C6 alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7,SOR10, SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, anoptionally further substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein: ∘R4 is hydrogen,C2-C6 alkenyl, C2-C6 alkynyl, NR5R6, OR7, SR7, R8R9N—C1-C6 alkyl,R8O—C1-C6 alkyl, an optionally further substituted straight or branchedC1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl; R5 andR6 are independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, R8R9N—C2-C6alkyl, R8O—C2-C6 alkyl, an optionally further substituted straight orbranched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, aryl orheteroaryl, or R5 and R6, taken together with the nitrogen atom to whichthey are bonded, may form an optionally substituted heterocyclyl group;

∘R7 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, COR4, SOR10, SO2R10,R8R9N—C2-C6 alkyl, R8O—C2-C6 alkyl, an optionally further substitutedstraight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, arylor heteroaryl, wherein R4 is as defined above;

∘R8 and R9 are independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl,COR4, an optionally further substituted straight or branched C1-C6alkyl, C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl, or R8 and R9,taken together with the nitrogen atom to which they are bonded, may forman optionally substituted heterocyclyl group, wherein R4 is as definedabove;

∘R10 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, NR5R6, OR7, R8R9N—C1-C6alkyl, R8O—C1-C6 alkyl, an optionally further substituted straight orbranched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, aryl orheteroaryl, wherein R5, R6, R7, R8 and R9 are as defined above;

●R is an optionally substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl, aryl or heteroaryl;

●R1, R2 and R3 are independently hydrogen, halogen, nitro, an optionallysubstituted straight or branched C1-C6 alkyl, NR5R6, or OR7, wherein R5,R6 and R7 are as defined above; or isomers, tautomers, prodrugs orpharmaceutically acceptable salt thereof.

Several indazole derivatives useful for the therapy of a variety ofdiseases such as cancer, neurodegenerative, cardiovascular, metabolicand of the central nervous system, have been disclosed in WO2007075847in the name of Takeda Pharmaceutical, in WO2006003276, WO2004062662,WO2004022544 and WO2003078403 all in the name of Aventis, inWO2006080450 in the name of Kyowa Hakko Kogyo and in WO2006003276 in thename of University of Connecticut.

Despite these developments, there is still need for effective agents forsaid diseases. The present inventors have now discovered that compoundsof formula 2.(I), described below, are kinase inhibitors and are thususeful in therapy as antitumor agents.

More particularly, a second object of the present invention is toprovide a substituted indazole compound represented by formula 2.(I),

Wherein Ar is aryl optionally substituted with one or more substituentsindependently selected from halogen, alkenyl, alkynyl, cyano, nitro,NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10, NHSOR10,NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, an optionally furthersubstituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl,heterocyclyl and aryl, wherein:

R4 is hydrogen, alkenyl, alkynyl, NR5R6, OR7, SR7, R8R9N—C1-C6 alkyl,R8O—C1-C6 alkyl, an optionally further substituted straight or branchedC1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl or aryl;

R5 and R6 are independently hydrogen, alkenyl, alkynyl, R8R9N—C2-C6alkyl, R8O—C2-C6 alkyl, an optionally further substituted straight orbranched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl or aryl, or R5 andR6, taken together with the nitrogen atom to which they are bonded, mayform an optionally substituted heterocyclyl group;

R7 is hydrogen, alkenyl, alkynyl, COR4, SOR10, SO2R10, R8R9N—C2-C6alkyl, R8O—C2-C6 alkyl, an optionally further substituted straight orbranched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl or aryl, wherein R4is as defined above;

R8 and R9 are independently hydrogen, alkenyl, alkynyl, COR4, anoptionally further substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl or aryl, or R8 and R9, taken together with thenitrogen atom to which they are bonded, may form an optionallysubstituted heterocyclyl group, wherein R4 is as defined above;

R10 is hydrogen, alkenyl, alkynyl, NR5R6, OR7, R8R9N—C1-C6 alkyl,R8O—C1-C6 alkyl, an optionally further substituted straight or branchedC1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl or aryl, wherein R5, R6, R7,R8 and R9 are as defined above; R is an optionally further substitutedstraight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl oraryl; R1, R2 and R3 are independently hydrogen, halogen, nitro, anoptionally further substituted straight or branched C1-C6 alkyl, NR5R6or OR7, wherein R5, R6 and R7 are as defined above; and pharmaceuticallyacceptable salt thereof.

The present invention also provides a method for treating diseasescaused by and/or associated with deregulated protein kinase activity,particularly PLK family, protein kinase C in different isoforms, Met,PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1,Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R,ALK, PI3K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7,Nek, Cdk/cyclin kinase family, more particularly Aurora 2, IGF-1R andALK activity, and ROS1 activity, and further more particularly ALKactivity and/or ROS1 activity, which comprises administering to a mammalin need thereof an effective amount of a substituted indazole compoundrepresented by formula (I) or formula 2.(I) as defined above.

Some embodiments of the present invention are to treat a disease causedby and/or associated with dysregulated protein kinase activity selectedfrom the group consisting of cancer and cell proliferative disorders.

Some embodiments of the present invention, are to treat specific typesof cancer including carcinoma, squamous cell carcinoma, hematopoietictumors of myeloid or lymphoid lineage, tumors of mesenchymal origin,tumors of the central and peripheral nervous system, melanoma, seminoma,teratocarcinoma, osteosarcoma, xeroderma pigmentosum, angiosarcoma,glioblastoma, holangiocarcinoma, inflammatory myofibroblastic tumor,epitheloid hemangioendothelioma, astrocytoma, meningioma, angiosarcoma,epitheloid hemangiothelioma, keratocanthomas, thyroid follicular cancer,Kaposi's sarcoma, and Pancreatic cancer.

Some embodiments of the present invention, are to treat specific typesof cancer such as, but not restricted to, breast cancer, lung cancer,colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer,gastric cancer, clear cell renal cell carcinoma, invasive ductalcarcinoma (breast), uveal melanoma, multiple myeloma, rhabdomyosarcoma,Ewing's sarcoma, Kaposi's sarcoma, Pancreatic cancer, andmedulloblastoma.

Some embodiments of the present invention, are to treat ALK+ AnaplasticLarge Cell Lymphomas (ALCL) and possibly other indications in which theALK activity might play a role, like Neuroblastoma, Rhabdomyosarcoma,Glioblastoma, Inflammatory Myofibroblastic Tumor, and some kind ofMelanomas, Breast Carcinomas, Ewings sarcomas, Retinoblastomas and NonSmall Cell Lung Carcinomas (NSCLC).

Some embodiments of the present invention, are to treat, reduce thesymptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule of Formula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

Some embodiments of the present invention, are to treat, reduce thesymptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule disclosed in U.S. Pat. No. 8,299,057, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, which patent issued Oct. 30, 2012, the entirety of which ishereby incorporated by reference. Some embodiments of the presentinvention, are to treat, reduce the symptoms of, ameliorate the symptomsof, delay the onset of, or otherwise pharmaceutically address Pancreaticcancer and possibly other indications in which a defect in themodulation of ROS1 activity, or upregulation, misregulation or deletionthereof might play a role by administering a molecule disclosed in U.S.Pat. No. 8,114,865, such asN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, which patent issued Feb. 14, 2012, the entirety of which ishereby incorporated by reference.

Some embodiments of the present invention, are to treat, reduce thesymptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address Pancreatic cancer and possibly otherindications in which a defect in the modulation of ALK, ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering amolecule disclosed in U.S. Pat. No. 8,299,057, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, which patent issued Oct. 30, 2012, the entirety of which ishereby incorporated by reference. Some embodiments of the presentinvention, are to treat, reduce the symptoms of, ameliorate the symptomsof, delay the onset of, or otherwise pharmaceutically address Pancreaticcancer and possibly other indications in which a defect in themodulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, or upregulation, misregulation or deletion thereof might play arole by administering a molecule disclosed in U.S. Pat. No. 8,114,865,such asN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, which patent issued Feb. 14, 2012, the entirety of which ishereby incorporated by reference.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer and possiblyother indications in which a defect in the modulation of ROS1 activity,or upregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancer andpossibly other indications in which a defect in the modulation of ROS1activity, or upregulation, misregulation or deletion thereof might playa role by administering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancer andpossibly other indications in which a defect in the modulation of ROS1activity, or upregulation, misregulation or deletion thereof might playa role by administering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer and possiblyother indications in which a defect in the modulation of ALK, ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering amolecule of U.S. Pat. No. 8,299,057, issued Oct. 30, 2012, the entiretyof which is hereby incorporated by reference. In some embodiments,methods of the present invention are to treat, reduce the symptoms of,ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering amolecule of U.S. Pat. No. 8,114,865, issued Feb. 14, 2012, the entiretyof which is hereby incorporated by reference.

In some embodiments, methods of the present invention are treat, reducethe symptoms of, ameliorate the symptoms of, delay the onset of, orotherwise pharmaceutically address Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering amolecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancer andpossibly other indications in which a defect in the modulation of ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancer andpossibly other indications in which a defect in the modulation of ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer associated witha ROS1 down-regulation defect, for example a null mutation such as aROS1 deletion by identifying a ROS1 down-regulation defect, for examplea null mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an individual, and administering to the individual amolecule of Formula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancerassociated with a ROS1 down-regulation defect, for example a nullmutation such as a ROS1 deletion by identifying a ROS1 down-regulationdefect, for example a null mutation such as a ROS1 deletion in a canceror precancerous pancreatic cell in an individual, and administering tothe individual a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancerassociated with a ROS1 down-regulation defect, for example a nullmutation such as a ROS1 deletion by identifying a ROS1 down-regulationdefect, for example a null mutation such as a ROS1 deletion in a canceror precancerous pancreatic cell in an individual, and administering tothe individual a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer associated witha ALK, ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example anull mutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion byidentifying a ALK, ROS1, TrkA, TrkB, or TrkC down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion in a cancer or precancerous pancreatic cell in an individual,and administering to the individual a molecule of Formula (I) asdisclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an individual comprises assaying for ROS1 activity in a cellextract from a pancreatic cancerous or precancerous cell population. Insome embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an individual comprises assaying for ROS1 transcriptaccumulation in an RNA population from a pancreatic cancerous orprecancerous cell population. In some embodiments identifying a ROS1modulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ROS1 deletion or a ROS1chimeric locus encoding a constitutively active ROS1 kinase in a canceror precancerous pancreatic cell in an individual comprises determiningthe nucleic acid sequence such as the genomic deoxyribonucleic acidsequence in a cell or cells or a cell population comprising a cell orcells from a pancreatic cancerous or precancerous cell population.

In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an individual comprisesassaying for ALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extractfrom a pancreatic cancerous or precancerous cell population. In someembodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkC modulationdefect such as an upregulation defect or a down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locus encoding aconstitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinase in a canceror precancerous pancreatic cell in an individual comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC transcript accumulation in an RNApopulation from a pancreatic cancerous or precancerous cell population.In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an individual comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer and possiblyother indications in which a defect in the modulation of ALK, ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, or upregulation,misregulation or deletion thereof might play a role by administering amolecule of U.S. Pat. No. 8,299,057, issued Oct. 30, 2012, the entiretyof which is hereby incorporated by reference. In some embodiments,methods of the present invention are to treat, reduce the symptoms of,ameliorate the symptoms of, delay the onset of, or otherwisepharmaceutically address Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering amolecule of U.S. Pat. No. 8,114,865, issued Feb. 14, 2012, the entiretyof which is hereby incorporated by reference.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer and possiblyother indications in which a defect in the modulation of ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancer andpossibly other indications in which a defect in the modulation of ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancer andpossibly other indications in which a defect in the modulation of ROS1,TrkA, TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer associated witha ROS1 down-regulation defect, for example a null mutation such as aROS1 deletion by identifying a ROS1 down-regulation defect, for examplea null mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an individual, and administering to the individual amolecule of Formula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancerassociated with a ROS1 down-regulation defect, for example a nullmutation such as a ROS1 deletion by identifying a ROS1 down-regulationdefect, for example a null mutation such as a ROS1 deletion in a canceror precancerous pancreatic cell in an individual, and administering tothe individual a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address Pancreatic cancerassociated with a ROS1 down-regulation defect, for example a nullmutation such as a ROS1 deletion by identifying a ROS1 down-regulationdefect, for example a null mutation such as a ROS1 deletion in a canceror precancerous pancreatic cell in an individual, and administering tothe individual a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address Pancreatic cancer associated witha ALK, ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example anull mutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion byidentifying a ALK, ROS1, TrkA, TrkB, or TrkC down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion in a cancer or precancerous pancreatic cell in an individual,and administering to the individual a molecule of Formula (I) asdisclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an individual comprises assaying for ROS1 activity in a cellextract from a pancreatic cancerous or precancerous cell population. Insome embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous pancreaticcell in an individual comprises assaying for ROS1 transcriptaccumulation in an RNA population from a pancreatic cancerous orprecancerous cell population. In some embodiments identifying a ROS1modulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ROS1 deletion or a ROS1chimeric locus encoding a constitutively active ROS1 kinase in a canceror precancerous pancreatic cell in an individual comprises determiningthe nucleic acid sequence such as the genomic deoxyribonucleic acidsequence in a cell or cells or a cell population comprising a cell orcells from a pancreatic cancerous or precancerous cell population.

In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an individual comprisesassaying for ALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extractfrom a pancreatic cancerous or precancerous cell population. In someembodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkC modulationdefect such as an upregulation defect or a down-regulation defect, forexample a null mutation such as a ALK, ROS1, TrkA, TrkB, or TrkCdeletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locus encoding aconstitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinase in a canceror precancerous pancreatic cell in an individual comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC transcript accumulation in an RNApopulation from a pancreatic cancerous or precancerous cell population.In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous pancreatic cell in an individual comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address a condition selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer and possibly other indicationsin which a defect in the modulation of ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, or upregulation, misregulation ordeletion thereof might play a role by administering a molecule of U.S.Pat. No. 8,299,057, issued Oct. 30, 2012, the entirety of which ishereby incorporated by reference. In some embodiments, methods of thepresent invention are to treat, reduce the symptoms of, ameliorate thesymptoms of, delay the onset of, or otherwise pharmaceutically addressPancreatic cancer and possibly other indications in which a defect inthe modulation of ROS1, TrkA, TrkB, or TrkC activity, or a combinationthereof, activity, or upregulation, misregulation or deletion thereofmight play a role by administering a molecule of U.S. Pat. No.8,114,865, issued Feb. 14, 2012, the entirety of which is herebyincorporated by reference.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address a condition selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer and possibly other indicationsin which a defect in the modulation of ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, activity, or upregulation,misregulation or deletion thereof might play a role by administering amolecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address a condition selectedfrom non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer and colorectal cancer and possiblyother indications in which a defect in the modulation of ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address a condition selectedfrom non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer and colorectal cancer and possiblyother indications in which a defect in the modulation of ROS1, TrkA,TrkB, or TrkC activity, or a combination thereof, activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address a condition selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerous cellin an individual, and administering to the individual a molecule ofFormula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention aretreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address a condition selectedfrom non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer and colorectal cancer associated with aROS1 down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerous cellin an individual, and administering to the individual a molecule whichisN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. In some embodiments, methods of the present invention are totreat, reduce the symptoms of, ameliorate the symptoms of, delay theonset of, or otherwise pharmaceutically address a condition selectedfrom non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer and colorectal cancer associated with aROS1 down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerous cellin an individual, and administering to the individual a molecule whichisN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments, methods of the present invention are to treat,reduce the symptoms of, ameliorate the symptoms of, delay the onset of,or otherwise pharmaceutically address a condition selected fromnon-small cell lung cancer, papillary thyroid cancer, neuroblastoma,pancreatic cancer and colorectal cancer associated with a ALK, ROS1,TrkA, TrkB, or TrkC down-regulation defect, for example a null mutationsuch as a ALK, ROS1, TrkA, TrkB, or TrkC deletion by identifying a ALK,ROS1, TrkA, TrkB, or TrkC down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion in a canceror precancerous cell in an individual, and administering to theindividual a molecule of Formula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

In some embodiments identifying a ROS1 modulation defect such as anupregulation defect or a down-regulation defect, for example a nullmutation such as a ROS1 deletion or a ROS1 chimeric locus encoding aconstitutively active ROS1 kinase in a cancer or precancerous cell in anindividual comprises assaying for ROS1 activity in a cell extract from apancreatic cancerous or precancerous cell population. In someembodiments identifying a ROS1 modulation defect such as an upregulationdefect or a down-regulation defect, for example a null mutation such asa ROS1 deletion or a ROS1 chimeric locus encoding a constitutivelyactive ROS1 kinase in a cancer or precancerous cell in an individualcomprises assaying for ROS1 transcript accumulation in an RNA populationfrom a cancerous or precancerous cell population. In some embodimentsidentifying a ROS1 modulation defect such as an upregulation defect or adown-regulation defect, for example a null mutation such as a ROS1deletion or a ROS1 chimeric locus encoding a constitutively active ROS1kinase in a cancer or precancerous cell in an individual comprisesdetermining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a pancreatic cancerous or precancerouscell population.

In some embodiments identifying a ALK, ROS1, TrkA, TrkB, or TrkCmodulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ALK, ROS1, TrkA, TrkB, orTrkC deletion or a ALK, ROS1, TrkA, TrkB, or TrkC chimeric locusencoding a constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinasein a cancer or precancerous cell in an individual comprises assaying forALK, ROS1, TrkA, TrkB, or TrkC activity in a cell extract from acancerous or precancerous cell population. In some embodimentsidentifying a ALK, ROS1, TrkA, TrkB, or TrkC modulation defect such asan upregulation defect or a down-regulation defect, for example a nullmutation such as a ALK, ROS1, TrkA, TrkB, or TrkC deletion or a ALK,ROS1, TrkA, TrkB, or TrkC chimeric locus encoding a constitutivelyactive ALK, ROS1, TrkA, TrkB, or TrkC kinase in a cancer or precancerouscell in an individual comprises assaying for ALK, ROS1, TrkA, TrkB, orTrkC transcript accumulation in an RNA population from a cancerous orprecancerous cell population. In some embodiments identifying a ALK,ROS1, TrkA, TrkB, or TrkC modulation defect such as an upregulationdefect or a down-regulation defect, for example a null mutation such asa ALK, ROS1, TrkA, TrkB, or TrkC deletion or a ALK, ROS1, TrkA, TrkB, orTrkC chimeric locus encoding a constitutively active ALK, ROS1, TrkA,TrkB, or TrkC kinase in a cancer or precancerous cell in an individualcomprises determining the nucleic acid sequence such as the genomicdeoxyribonucleic acid sequence in a cell or cells or a cell populationcomprising a cell or cells from a cancerous or precancerous cellpopulation.

In some embodiments, methods of the present invention are to treat cellproliferative disorders such as, but not restricted to, benign prostatehyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,psoriasis, atherosclerosis and conditions involving vascular smoothmuscle proliferation or neointimal formation such as restenosisfollowing angioplasty or surgery, pulmonary fibrosis, arthritis,glomerulonephritis, retinopathies including diabetic and neonatalretinopathies and age related macular degeneration, graft vesseldisease, such as can occur following vessel or organ transplantation,acromegaly and disorders secondary to acromegaly as well as otherhypertrophic conditions in which IGF/IGF-1R signaling is implicated,such as fibrotic lung disease, pathologies related to chronic or acuteoxidative stress or hyperoxia induced tissue damage, and metabolicdisorders in which elevated IGF levels or IGF-1R activity areimplicated, such as obesity.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition.

In some embodiments, the method of the present invention furthercomprises subjecting the mammal in need thereof to a radiation therapyor chemotherapy regimen in combination with at least one cytostatic orcytotoxic agent. Moreover the invention provides a method for inhibitingthe activity ALK protein which comprises contacting the said proteinwith an effective amount of a compound of formula (I) or formula 2.(I).

In some embodiments, methods of the present invention are for inhibitingat least one of ALK, ROS1, TrkA, TrkB, or TrkC kinase activity, or acombination thereof, in a cell, comprising contacting said cell with aneffective amount of a compound disclosed herein. Some embodimentsprovide methods of inhibiting at least one of ALK, ROS1, TrkA, TrkB, orTrkC kinase activity, or a combination thereof, in a cell, comprisingcontacting said cell with an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. Some embodiments provide methods of inhibiting at least oneof ALK, ROS1, TrkA, TrkB, or TrkC kinase activity, or a combinationthereof, in a cell, comprising contacting said cell with an effectiveamount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide. Some embodiments provide methods of inhibiting at least oneof ALK, ROS1, TrkA, TrkB, or TrkC kinase activity, or a combinationthereof, in a cell, comprising contacting said cell with an effectiveamount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

The present invention also provides a pharmaceutical compositioncomprising one or more compounds of formula (I) or formula 2.(I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient, carrier or diluent. Some embodiments provide apharmaceutical composition comprising one or more compounds selectedfromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide andN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient, carrier or diluent. Someembodiments provide a pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient, carrier or diluent. Someembodiments provide a pharmaceutical composition comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient, carrier or diluent.

Some embodiments provide methods of inhibiting ALK, ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, in a patient, comprisingadministering to said patient an effective amount of a compound selectedfromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of inhibiting ALK, ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, in a patient, comprisingadministering to said patient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of inhibiting ALK, ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, in a patient, comprisingadministering to said patient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of inhibiting ALK, ROS1, TrkA, TrkB, orTrkC activity, or a combination thereof, in a patient, comprisingadministering to said patient an effective amount of a compound which isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient in needthereof, the method comprising inhibiting ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, in said patient, by administering tosaid patient an effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient in needthereof, the method comprising inhibiting ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, in said patient, by administering tosaid patient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient in needthereof, the method comprising inhibiting ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, in said patient, by administering tosaid patient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient in needthereof, the method comprising inhibiting ALK, ROS1, TrkA, TrkB, or TrkCactivity, or a combination thereof, in said patient, by administering tosaid patient an effective amount of a compound which isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating non-small cell lung cancer,papillary thyroid cancer, neuroblastoma, pancreatic cancer or colorectalcancer in a patient, comprising administering to said patient aneffective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating tumors in a patient, saidmethods comprising administering to the patient an effective amount of acompound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods wherein the tumors are caused by thepresence of non-small cell lung cancer, papillary thyroid cancer,neuroblastoma, pancreatic cancer or colorectal cancer in the patient.Some embodiments provide methods wherein one or more of the cellscomprising the tumors in the patient test positive for the presence of agene that expresses at least one of ALK, ROS1, TrkA, TrkB, or TrkCkinase or one or more of the cells comprising the tumors in said patientdemonstrates at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinaseactivity.

Some embodiments provide methods wherein one or more of the cellscomprising the tumors in the patient test positive for at least one generearrangement comprising the gene, or a fragment thereof, that expressesat least one of ALK, ROS1, TrkA, TrkB, or TrkC kinase. Some embodimentsprovide such methods wherein the cells test positive for at least one ofROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide methodswherein the cells test positive for ROS1 kinase. Some embodimentsprovide methods wherein the cells test positive for at least one ofTrkA, TrkB and TrkC kinase. Some embodiments provide methods wherein thecells test positive for TrkA kinase. Some embodiments provide methodswherein the cells test positive for TrkB kinase. Some embodimentsprovide such methods wherein the cells test positive for TrkC kinase.

Some embodiments provide methods of treating cancer in a patient, themethod comprising: (1) testing one or more cells comprising the tumorsin the patient for the presence of at least one of ALK, ROS1, TrkA,TrkB, or TrkC kinase; and (2) administering to the patient an effectiveamount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, if said one ormore cells tests positive for at least one of ALK, ROS1, TrkA, TrkB, orTrkC kinase.

Some embodiments provide methods of treating cancer in a patient, themethod comprising: (1) testing one or more cells comprising the tumorsin the patient for the presence of at least one of ROS1, TrkA, TrkB, orTrkC kinase; and (2) administering to the patient an effective amount ofa compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, if said one ormore cells tests positive for at least one of ROS1, TrkA, TrkB, or TrkCkinase.

Some embodiments provide methods wherein the patient is administered aneffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods wherein the patient is administered aneffective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods wherein the patient is administered aneffective amount ofN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient,wherein one or more cancerous cells in said patient express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the patient an effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating cancer in a patient, wherein oneor more cancerous cells in said patient express at least one of ROS1,TrkA, TrkB, or TrkC kinase, the method comprising administering to thepatient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient,wherein one or more cancerous cells in said patient express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the patient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating cancer in a patient, wherein oneor more cancerous cells in said patient express at least one of ROS1,TrkA, TrkB, or TrkC kinase, the method comprising administering to thepatient an effective amount of a compound which isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient,wherein one or more cancerous cells in said patient express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the patient an effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating cancer in a patient, wherein oneor more cancerous cells in said patient express at least one of ROS1,TrkA, TrkB, or TrkC kinase, the method comprising administering to thepatient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating cancer in a patient,wherein one or more cancerous cells in said patient express at least oneof ROS1, TrkA, TrkB, or TrkC kinase, the method comprising administeringto the patient an effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating cancer in a patient, wherein oneor more cancerous cells in said patient express at least one of ROS1,TrkA, TrkB, or TrkC kinase, the method comprising administering to thepatient an effective amount of a compound which isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of treating a patient in which one ormore cancerous cells from said patient express at least one of ROS1,TrkA, TrkB, or TrkC kinase, the method comprising administering to thepatient an effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating a patient in which one or morecancerous cells from said patient express at least one of ROS1, TrkA,TrkB, or TrkC kinase, the method comprising administering to the patientan effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating a patient in which one or morecancerous cells from said patient express at least one of ROS1, TrkA,TrkB, or TrkC kinase, the method comprising administering to the patientan effective amount of a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods of treating a patient in which one or morecancerous cells from said patient express at least one of ROS1, TrkA,TrkB, or TrkC kinase, the method comprising administering to the patientan effective amount of a compound which isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating cancer, comprisingadministering to a patient in which one or more cancerous cells fromsaid patient express at least one of ROS1, TrkA, TrkB, or TrkC kinase aneffective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods wherein said compound isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof. Someembodiments provide methods wherein said compound isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some emobodiments provide a method for treating a patient having cancer,wherein tumors from said patient are ROS1, TrkA, TrkB, or TrkC positive,a combination thereof, the method comprising administering to thepatient an effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method for treating a patient having ROS1,TrkA, TrkB, or TrkC positive cancer, or a combination thereof, themethod comprising administering to the patient an effective amount of acompound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating a cancer patient,comprising (a) acquiring knowledge of the presence of at least onegenetic alteration in at least one target gene in the cancer patient,wherein the at least one target gene is selected from ALK1, BDNF, NGF,NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; (b) selecting acompound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, as a treatmentfor the cancer patient, based on the recognition that said compound iseffective in treating cancer patients having said at least one geneticalteration in said at least one target gene; and (c) administering atherapeutically effective amount of said compound to said cancerpatient.

Some embodiments provide a method of treating a cancer patient,comprising administering to said cancer patient a therapeuticallyeffective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, wherein priorto said administration of said compound, said cancer patient is known topossess at least one genetic alteration in at least one target geneselected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1,NTRK2, and NTRK3.

Some embodiments provide a method of treating cancer in a patient,comprising administering to said cancer patient known to possess atleast one genetic alteration in at least one target gene selected fromALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3a therapeutically effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating a cancer patient, whereinsaid cancer patient is known to possess at least one genetic alterationin at least one target gene, comprising administering to said cancerpatient a therapeutically effective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, and whereinsaid target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4,ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method of treating a cancer patient, whereinprior to said treatment said patient is known to possess at least onegenetic alteration in at least one target gene, comprising administeringto said cancer patient a therapeutically effective amount of a compoundselected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, and whereinsaid target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4,ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method of treating a cancer patient,comprising administering to said cancer patient a therapeuticallyeffective amount of a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof, and whereinprior to said compound being admininstered to said patient, said patientis known to possess at least one genetic alteration in at least onetarget gene selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1,SORT1, NTRK1, NTRK2, and NTRK3.

Some embodiments provide a method for treating a cancer patient,comprising (a) acquiring knowledge of the presence of at least onegenetic alteration in at least one target gene selected from ALK1, BDNF,NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; and (b)administering to said patient a therapeutically effective amount of acompound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments provide any of the methods described herein wherein thepatient or subject is suffering from cancer and the cancer is selectedfrom at least one of non-small cell lung cancer, papillary thyroidcancer, neuroblastoma, pancreatic cancer and colorectal cancer.

Some embodiments provide a pharmaceutical composition comprising acompound of formula (I) or formula 2.(I) in combination with one or morechemotherapeutic agents or radiotherapy, such as radiotherapy ascommonly administered to treat, ameliorate the symptoms of, or preventor delay the onset of cancer. Such agents can include, but are notlimited to, antihormonal agents such as antiestrogens, antiandrogens andaromatase inhibitors, topoisomerase I inhibitors, topoisomerase IIinhibitors, agents that target microtubules, platin-based agents,alkylating agents, DNA damaging or intercalating agents, antineoplasticantimetabolites, other kinase inhibitors, other anti-angiogenic agents,inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors ofmTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors,and inhibitors of hypoxic response.

Some embodiments provide a product or kit comprising a compound offormula (I) or formula 2.(I) or a pharmaceutically acceptable saltthereof, as defined above, or pharmaceutical compositions thereof andone or more chemotherapeutic agents, as a combined preparation forsimultaneous, separate or sequential use in anticancer therapy. Someembodiments provide a product or kit comprising a compound selected fromN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide andN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof, orpharmaceutical compositions thereof and one or more chemotherapeuticagents, as a combined preparation for simultaneous, separate orsequential use in anticancer therapy.

Some embodiments provide a product or kit comprising a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof, orpharmaceutical compositions thereof and one or more chemotherapeuticagents, as a combined preparation for simultaneous, separate orsequential use in anticancer therapy. Some embodiments provide a productor kit comprising a compound which isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof, orpharmaceutical compositions thereof and one or more chemotherapeuticagents, as a combined preparation for simultaneous, separate orsequential use in anticancer therapy.

Some embodiments provide a compound of formula (I) or formula 2.(I) or apharmaceutically acceptable salt thereof, as defined above, for use as amedicament.

Some embodiments provide the use of a compound of formula (I) or formula2.(I) or a pharmaceutically acceptable salt thereof, as defined above,in the manufacture of a medicament with antitumor activity.

Some embodiments provide a compound of formula (I) or formula 2.(I) or apharmaceutically acceptable salt thereof, as defined above, for use in amethod of treating cancer. Some embodiments may be further summarized byreference to the numerically listed embodiments recited below:

-   -   1. A method of treating, ameliorating the symptoms of, delaying        the onset of or delaying the progression of cancer comprising        the steps of    -   determining whether modulation of ROS1 activity is defective in        a cell population of an individual, and if said modulation of        ROS1 activity is defective,    -   administering a molecule of a selected from the list consisting        of formula (I) and formula 2.(I) to said individual,    -   thereby treating, ameliorating the symptoms of, delaying the        onset of or delaying the progression of cancer.    -   2. The method of embodiment 1, wherein said determining whether        modulation of ROS1 activity is defective comprises assaying for        ROS1 kinase activity in an extract of a cell population of said        individual.    -   3. The method of embodiment 1, wherein said determining whether        modulation of ROS1 activity is defective comprises assaying for        transcript accumulation in an extract comprising RNA of a cell        population of said individual.    -   4. The method of embodiment 1, wherein said determining whether        modulation of ROS1 activity is defective comprises sequencing a        ROS1 locus in the genomic DNA of a cell population of said        individual.    -   5. The method of embodiment 4, wherein said defective modulation        of ROS1 activity comprises upregulation of ROS1 activity.    -   6. The method of embodiment 5, wherein a fusion of a coding        region of a second protein at the ROS1 locus indicates        upregulation of ROS1 kinase activity.    -   7. The method of embodiment 4, wherein said defective modulation        of ROS1 activity comprises a reduction of ROS1 activity to a        lower level.    -   8. The method of embodiment 7, wherein a null mutation of said        ROS1 locus indicates that ROS1 activity is reduced.    -   9. The method of embodiment 7, wherein said null mutation        comprises an insertion.    -   10. The method of embodiment 7, wherein said null mutation        comprises a frame shift of a coding region encoding ROS1.    -   11. The method of embodiment 7, wherein said null mutation        comprises a deletion within the locus encoding ROS1.    -   12. The method of embodiment 7, wherein said null mutation        comprises a deletion of the nucleic acid sequence spanning the        ROS1 locus.    -   13. The method of embodiment 7, wherein a mutation affecting        accumulation of ROS1 mRNA indicates that ROS1 activity is        reduced.    -   14. The method of any of embodiments 1-13, wherein said molecule        is a molecule of formula (I).    -   15. The method of any of embodiments 1-13, wherein said molecule        is a molecule of formula 2.(I).    -   16. The method of any of embodiments 1-13, wherein said molecule        is        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide    -   17. The method of any of embodiments 1-13, wherein said molecule        is        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide.    -   18. The method of any of embodiments 1-13, wherein said molecule        is        N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)        benzamide.    -   19. The method of any of embodiments 1-18, wherein said cancer        comprises pancreatic cancer.    -   20. The method of any of embodiments 1-19, further comprising        administering radiotherapy to said individual.

Some additional embodiments may be further summarized by reference tothe numerically listed embodiments recited below:

-   -   1. The use of a compound selected from the group consisting of        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide,        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, and        N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)        benzamide, or a pharmaceutically acceptable salt thereof, for        preparing a medicament for treating cancer in a patient, wherein        said cancer patient has at least one genetic alteration in at        least one target gene selected from ROS1, NTRK1, NTRK2, and        NTRK3.    -   2. Use according to embodiment 1, wherein said at least one        target gene is ROS1.    -   3. Use according to embodiment 1, wherein said at least one        target gene is selected from the group consisting of NTRK1,        NTRK2, and NTRK3.    -   4. Use according to embodiment 1, wherein said compound is        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, or a pharmaceutically acceptable salt thereof.    -   5. Use according to embodiment 4, wherein said at least one        target gene is ROS1.    -   6. Use according to embodiment 4, wherein said at least one        target gene is selected from the group consisting of NTRK1,        NTRK2, and NTRK3.    -   7. Use according to embodiment 1, wherein said compound is        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, or a pharmaceutically acceptable salt thereof.    -   8. Use according to embodiment 7, wherein said at least one        target gene is ROS1.    -   9. Use according to embodiment 7, wherein said at least one        target gene is selected from the group consisting of NTRK1,        NTRK2, and NTRK3.    -   10. Use according to embodiment 1, wherein said compound is        N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)        benzamide, or a pharmaceutically acceptable salt thereof.    -   11. Use according to embodiment 10, wherein said at least one        target gene is ROS1.    -   12. Use according to embodiment 10, wherein said at least one        target gene is selected from the group consisting of NTRK1,        NTRK2, and NTRK3.    -   13. Use according to embodiment 1, wherein said cancer is        selected from the group consisting of non-small cell lung        cancer, papillary thyroid cancer, neuroblastoma, pancreatic        cancer and colorectal cancer.    -   14. Use according to embodiment 1, wherein said compound is        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, or a pharmaceutically acceptable salt thereof, and        said cancer is selected from the group consisting of non-small        cell lung cancer, papillary thyroid cancer, neuroblastoma,        pancreatic cancer and colorectal cancer.    -   15. Use according to embodiment 14, wherein said cancer is        selected from the group consisting of non-small cell lung        cancer, neuroblastoma and colorectal cancer.    -   16. Use according to embodiment 1, wherein said compound is        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, or a pharmaceutically acceptable salt thereof, and        said cancer is selected from the group consisting of non-small        cell lung cancer, papillary thyroid cancer, neuroblastoma,        pancreatic cancer and colorectal cancer.    -   17. Use according to embodiment 16, wherein said cancer is        selected from the group consisting of non-small cell lung        cancer, neuroblastoma and colorectal cancer.    -   18. Use according to embodiment 1, wherein said compound is        N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)        benzamide, or a pharmaceutically acceptable salt thereof, and        said cancer is selected from the group consisting of non-small        cell lung cancer, papillary thyroid cancer, neuroblastoma,        pancreatic cancer and colorectal cancer.    -   19. Use according to embodiment 18, wherein said cancer is        selected from the group consisting of non-small cell lung        cancer, neuroblastoma and colorectal cancer.    -   20. A compound selected from the group consisting of        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide,        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, and        N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)        benzamide, or a pharmaceutically acceptable salt thereof, for        use in method of treating cancer in a patient having at least        one genetic alteration in at least one target gene selected from        the group consisting of ROS1, NTRK1, NTRK2, and NTRK3, wherein        said method comprises the steps of:    -   a) determining whether said patient has at least one genetic        alteration in at least one target gene selected from the group        consisting of ROS1, NTRK1, NTRK2, and NTRK3; and    -   b) administering a therapeutically effective amount of said        compound to said cancer patient.    -   21. A compound for use according to embodiment 20, wherein said        cancer is selected from the group consisting of non-small cell        lung cancer, papillary thyroid cancer, neuroblastoma, pancreatic        cancer and colorectal cancer.    -   22. A method of treating cancer in a patient, wherein said        patient is known to possess at least one genetic alteration in        at least one target gene selected from ROS1, NTRK1, NTRK2, and        NTRK3, comprising administering to said cancer patient a        therapeutically effective amount of a compound selected from        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide,        N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)        benzamide, and        N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)        benzamide, or a pharmaceutically acceptable salt thereof.

Some embodiments include any of the methods described herein, whereinsaid cancer is selected from non-small cell lung cancer, papillarythyroid cancer, neuroblastoma, pancreatic cancer and colorectal cancer.Some embodiments are any of the methods described herein wherein saidcancer is non-small cell lung cancer. Some embodiments include any ofthe methods described herein, wherein said cancer is said cancer ispapillary thyroid cancer. Some embodiments include any of the methodsdescribed herein, wherein said cancer is wherein said cancer isneuroblastoma. Some embodiments include any of the methods describedherein, wherein said cancer is wherein said cancer is pancreatic cancer.Some embodiments include any of the methods described herein, whereinsaid cancer is wherein said cancer is colorectal cancer.

Some embodiments include any of the methods described herein, whereinany of the compounds described herein are administered to saidindividual in an amount ranging from about 200 mg/m² to about 1600mg/m², or from about 200 mg/m² to about 1200 mg/m², or from about 200mg/m² to about 1000 mg/m², or from about 400 mg/m² to about 1200 mg/m²,or from about 400 mg/m² to about 1000 mg/m², or from about 800 mg/m² toabout 1000 mg/m², or from about 800 mg/m² to about 1200 mg/m², or fromabout 800 mg/m² to about 1200 mg/m², or from about 800 mg/m² to about1600 mg/m². Some embodiments include any of the methods describedherein, wherein any of the compounds described herein are administeredto said individual in an amount of about 200 mg/m², about 300 mg/m²,about 400 mg/m², about 500 mg/m², about 600 mg/m², about 700 mg/m²,about 800 mg/m², about 900 mg/m², about 1000 mg/m², about 1100 mg/m²,about 1200 mg/m², about 1300 mg/m², about 1400 mg/m², about 1500 mg/m²,about 1600 mg/m², about 1700 mg/m², about 1800 mg/m², about 1900 mg/m²,or about 2000 mg/m².

Some embodiments relate to the use of any of the compounds as describedherein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of abnormal cell growth ina mammal. The present invention further relates to the use of any of thecompounds as described herein, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment ofabnormal cell growth in a mammal wherein the abnormal cell growth iscancerous or non-cancerous. In some embodiments, the abnormal cellgrowth is cancerous. In another embodiment, the abnormal cell growth isnon-cancerous.

Some embodiments relate to any of the compounds described herein, orpharmaceutically acceptable salts thereof, for use as a medicament. Someembodiments relate to the use of any of the compounds described above,or pharmaceutically acceptable salts thereof, for the manufacture of amedicament for the treatment of abnormal cell growth.

As used herein “cancer” refers to any malignant and/or invasive growthor tumor caused by abnormal cell growth. As used herein “cancer” refersto solid tumors named for the type of cells that form them, cancer ofblood, bone marrow, or the lymphatic system. Examples of solid tumorsinclude but are not limited to sarcomas and carcinomas. Examples ofcancers of the blood include but are not limited to leukemias, lymphomasand myeloma. The term “cancer” includes but is not limited to a primarycancer that originates at a specific site in the body, a metastaticcancer that has spread from the place in which it started to other partsof the body, a recurrence from the original primary cancer afterremission, and a second primary cancer that is a new primary cancer in aperson with a history of previous cancer of different type from latterone.

Some embodiments relate to compositions comprising a compound of FormulaI or a pharmaceutically acceptable salt thereof (e.g., pharmaceuticalcompositions). Accordingly, in some embodiments, the invention relatesto a pharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt, a pharmaceutically acceptable carrierand, optionally, at least one additional medicinal or pharmaceuticalagent. In some embodiments, the at least one additional medicinal orpharmaceutical agent is an anti-cancer agent as described below.

The pharmaceutically acceptable carrier may comprise a conventionalpharmaceutical carrier or excipient. Suitable pharmaceutical carriersinclude inert diluents or fillers, water and various organic solvents(such as hydrates and solvates). The pharmaceutical compositions may, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Non-limiting examples ofmaterials, therefore, include lactose or milk sugar and high molecularweight polyethylene glycols. When aqueous suspensions or elixirs aredesired for oral administration the active compound therein may becombined with various sweetening or flavoring agents, coloring mattersor dyes and, if desired, emulsifying agents or suspending agents,together with diluents such as water, ethanol, propylene glycol,glycerin, or combinations thereof.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution suspension, for parenteral injection as asterile solution, suspension or emulsion, for topical administration asan ointment or cream or for rectal administration as a suppository.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms may be suitably buffered, if desired.

The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages.

In some embodiments, the composition comprises a therapeuticallyeffective amount of a compound as disclosed herein and apharmaceutically acceptable carrier.

The compounds of the present invention may be formulated intopharmaceutical compositions as described below in any pharmaceuticalform recognizable to the skilled artisan as being suitable.Pharmaceutical compositions of the invention comprise a therapeuticallyeffective amount of at least one compound disclosed herein and an inert,pharmaceutically acceptable carrier or diluent.

To treat or prevent diseases or conditions mediated by ALK, ROS1, TrkA,TrkB, or TrkC, or a combination thereof, a pharmaceutical composition ofthe invention is administered in a suitable formulation prepared bycombining a therapeutically effective amount (i.e., a ALK, ROS1, TrkA,TrkB, or TrkC modulating, regulating, or inhibiting amount effective toachieve therapeutic efficacy) of at least one compound of the presentinvention (as an active ingredient) with one or more pharmaceuticallysuitable carriers, which may be selected, for example, from diluents,excipients and auxiliaries that facilitate processing of the activecompounds into the final pharmaceutical preparations.

The pharmaceutical carriers employed may be either solid or liquid.Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryliquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the inventive compositions may include time-delay ortime-release material known in the art, such as glyceryl monostearate orglyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate or the like. Furtheradditives or excipients may be added to achieve the desired formulationproperties. For example, a bioavailability enhancer, such as Labrasol,Gelucire or the like, or formulator, such as CMC(carboxy-methylcellulose), PG (propyleneglycol), or PEG(polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle thatprotects active ingredients from light, moisture and oxidation, may beadded, e.g., when preparing a capsule formulation.

If a solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form, or formed into a trocheor lozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of syrup, emulsion, soft gelatin capsule,sterile injectable solution or suspension in an ampoule or vial ornon-aqueous liquid suspension. If a semi-solid carrier is used, thepreparation may be in the form of hard and soft gelatin capsuleformulations. The inventive compositions are prepared in unit-dosageform appropriate for the mode of administration, e.g. parenteral or oraladministration.

To obtain a stable water-soluble dose form, a salt of a compound of thepresent invention may be dissolved in an aqueous solution of an organicor inorganic acid, such as a 0.3 M solution of succinic acid or citricacid. If a soluble salt form is not available, the agent may bedissolved in a suitable co-solvent or combinations of co-solvents.Examples of suitable co-solvents include alcohol, propylene glycol,polyethylene glycol 300, polysorbate 80, glycerin and the like inconcentrations ranging from 0 to 60% of the total volume. In anexemplary embodiment, a compound of the present invention is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

Proper formulation is dependent upon the route of administrationselected. For injection, the agents of the compounds of the presentinvention may be formulated into aqueous solutions, preferably inphysiologically compatible buffers such as Hanks solution, Ringer'ssolution, or physiological saline buffer. For transmucosaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers known inthe art. Such carriers enable the compounds of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a subject tobe treated. Pharmaceutical preparations for oral use can be obtainedusing a solid excipient in admixture with the active ingredient (agent),optionally grinding the resulting mixture, and processing the mixture ofgranules after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include: fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; and cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds of thepresent invention may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion-exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt. A pharmaceuticalcarrier for hydrophobic compounds is a co-solvent system comprisingbenzyl alcohol, a non-polar surfactant, a water-miscible organicpolymer, and an aqueous phase. The co-solvent system may be a VPDco-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol. The VPD co-solvent system(VPD: 5 W) contains VPD diluted 1:1 with a 5% dextrose in watersolution. This co-solvent system dissolves hydrophobic compounds well,and itself produces low toxicity upon systemic administration. Theproportions of a co-solvent system may be suitably varied withoutdestroying its solubility and toxicity characteristics. Furthermore, theidentity of the co-solvent components may be varied: for example, otherlow-toxicity non-polar surfactants may be used instead of polysorbate80; the fraction size of polyethylene glycol may be varied; otherbiocompatible polymers may replace polyethylene glycol, e.g. polyvinylpyrrolidone; and other sugars or polysaccharides may be substituted fordextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity due to the toxic nature of DMSO.Additionally, the compounds may be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. These carriers and excipients mayprovide marked improvement in the bioavailability of poorly solubledrugs. Examples of such carriers or excipients include calciumcarbonate, calcium phosphate, sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols. Furthermore,additives or excipients such as Gelucire®, Capryol®, Labrafil®,Labrasol®, Lauroglycol®, Plurol®, Peceol®, Transcutol® and the like maybe used.

Further, the pharmaceutical composition may be incorporated into a skinpatch for delivery of the drug directly onto the skin.

It will be appreciated that the actual dosages of the agents of thisinvention will vary according to the particular agent being used, theparticular composition formulated, the mode of administration, and theparticular site, host, and disease being treated. Those skilled in theart using conventional dosage-determination tests in view of theexperimental data for a given compound may ascertain optimal dosages fora given set of conditions. For oral administration, an exemplary dailydose generally employed will be from about 0.001 to about 1000 mg/kg ofbody weight, with courses of treatment repeated at appropriateintervals.

Furthermore, the pharmaceutically acceptable formulations of the presentinvention may contain a compound of the present invention, or a salt orsolvate thereof, in an amount of about 10 mg to about 2000 mg, or fromabout 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, orfrom about 10 mg to about 750 mg, or from about 10 mg to about 500 mg,or from about 25 mg to about 500 mg, or from about 50 to about 500 mg,or from about 100 mg to about 500 mg. Furthermore, the pharmaceuticallyacceptable formulations of the present invention may contain a compoundof the present invention, or a salt or solvate thereof, in an amount ofabout 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.

Additionally, the pharmaceutically acceptable formulations of thepresent invention may contain a compound of the present invention, or asalt or solvate thereof, in an amount from about 0.5 w/w % to about 95w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % toabout 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.

The compounds of the present invention, or salts or solvates thereof,may be administered to a mammal suffering from abnormal cell growth,such as a human, either alone or as part of a pharmaceuticallyacceptable formulation, once a day, twice a day, three times a day, orfour times a day, or even more frequently.

Those of ordinary skill in the art will understand that with respect tothe compounds of the present invention, the particular pharmaceuticalformulation, the dosage, and the number of doses given per day to amammal requiring such treatment, are all choices within the knowledge ofone of ordinary skill in the art and can be determined without undueexperimentation.

Administration of the compounds disclosed herein may be effected by anymethod that enables delivery of the compounds to the site of action.These methods include oral routes, intraduodenal routes, parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion), topical, and rectal administration.

Dosage regimens may be adjusted to provide the optimum desired response.For example, a single bolus may be administered, several divided dosesmay be administered over time or the dose may be proportionally reducedor increased as indicated by the exigencies of the therapeuticsituation. It is especially advantageous to formulate parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form, as used herein, refers tophysically discrete units suited as unitary dosages for the mammaliansubjects to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the chemotherapeuticagent and the particular therapeutic or prophylactic effect to beachieved, and (b) the limitations inherent in the art of compoundingsuch an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosureprovided herein, that the dose and dosing regimen is adjusted inaccordance with methods well-known in the therapeutic arts. That is, themaximum tolerable dose can be readily established, and the effectiveamount providing a detectable therapeutic benefit to a patient may alsobe determined, as can the temporal requirements for administering eachagent to provide a detectable therapeutic benefit to the patient.Accordingly, while certain dose and administration regimens areexemplified herein, these examples in no way limit the dose andadministration regimen that may be provided to a patient in practicingthe present invention.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Forexample, doses may be adjusted based on pharmacokinetic orpharmacodynamic parameters, which may include clinical effects such astoxic effects and/or laboratory values. Thus, the present inventionencompasses intra-patient dose-escalation as determined by the skilledartisan. Determining appropriate dosages and regimens for administrationof the chemotherapeutic agent are well-known in the relevant art andwould be understood to be encompassed by the skilled artisan onceprovided the teachings disclosed herein.

The compounds, compositions and methods provided herein are useful forthe treatment of cancers including but not limited to cancers of the:circulatory system, for example, heart (sarcoma [angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyoma,fibroma, lipoma and teratoma), mediastinum and pleura, and otherintrathoracic organs, vascular tumors and tumor-associated vasculartissue; respiratory tract, for example, nasal cavity and middle ear,accessory sinuses, larynx, trachea, bronchus and lung such as small celllung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogeniccarcinoma (squamous cell, undifferentiated small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;gastrointestinal system, for example, esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), gastric, pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); genitourinary tract, for example, kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia),bladder and/or urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); liver, for example, hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrinetumors (such as pheochromocytoma, insulinoma, vasoactive intestinalpeptide tumor, islet cell tumor and glucagonoma); bone, for example,osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; nervous system, for example, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, skull cancer (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosi s), brain cancer (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);reproductive system, for example, gynecological, uterus (endometrialcarcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia),ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma], granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma),vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma) and other sites associated with femalegenital organs; placenta, penis, prostate, testis, and other sitesassociated with male genital organs; hematologic system, for example,blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, for example,lip, tongue, gum, floor of mouth, palate, and other parts of mouth,parotid gland, and other parts of the salivary glands, tonsil,oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites inthe lip, oral cavity and pharynx; skin, for example, malignant melanoma,cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, and keloids; adrenal glands: neuroblastoma; and othertissues including connective and soft tissue, retroperitoneum andperitoneum, eye, intraocular melanoma, and adnexa, breast, head or/andneck, anal region, thyroid, parathyroid, adrenal gland and otherendocrine glands and related structures, secondary and unspecifiedmalignant neoplasm of lymph nodes, secondary malignant neoplasm ofrespiratory and digestive systems and secondary malignant neoplasm ofother sites.

More specifically, examples of “cancer” when used herein in connectionwith the present invention include cancer selected from lung cancer(NSCLC and SCLC), cancer of the head or neck, ovarian cancer, coloncancer, rectal cancer, prostate cancer, cancer of the anal region,stomachcancer, breast cancer, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, non-Hodgkins's lymphoma,spinal axis tumors, or a combination of one or more of the foregoingcancers.

In some embodiments, the compounds and the compositions disclosed hereinare useful for the treatment of cancers, including Spitz melanoma,perineural invasion, pulmonary large cell neuroendocrine carcinoma,uterine carcinoma, juvenile breast cancer, nasopharyngeal carcinoma,adenoid cystic cancer, meduallary thyroid cancer, salivary cancer,congenital infantile fibrosarcoma, mesoblastic nephroma, esophagealcancer (squamous), diffuse large B-cell lymphoma, papillary thyroidcancer, and mammary analogue secretory carcinoma.

In some embodiments, the compounds disclosed herein may be used incombination with one or more additional anti-cancer agents which aredescribed below. When a combination therapy is used, the one or moreadditional anti-cancer agents may be administered sequentially orsimultaneously with the compound of the invention. In some embodiments,the additional anti-cancer agent is administered to a mammal (e.g., ahuman) prior to administration of the compound of the invention. In someembodiments, the additional anti-cancer agent is administered to themammal after administration of the compound of the invention. In someembodiments, the additional anti-cancer agent is administered to themammal (e.g., a human) simultaneously with the administration of thecompound disclosed herein.

Some embodiments also relate to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human, whichcomprises an amount of a compound disclosed herein, as defined above(including hydrates, solvates and polymorphs of said compound orpharmaceutically acceptable salts thereof), in combination with one ormore (preferably one to three) anti-cancer agents selected from thegroup consisting of anti-angiogenesis agents and signal transductioninhibitors and a pharmaceutically acceptable carrier, wherein theamounts of the active agent and the combination anti-cancer agents whentaken as a whole is therapeutically effective for treating said abnormalcell growth.

In some embodiments, the anti-cancer agent used in conjunction with acompound disclosed herein and pharmaceutical compositions describedherein is an anti-angiogenesis agent (e.g., an agent that stops tumorsfrom developing new blood vessels). Examples of anti-angiogenesis agentsinclude for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors,PDGFR inhibitors, angiopoetin inhibitors, PKC.beta. inhibitors, COX-2(cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2(matrix-metalloprotienase 2) inhibitors, and MMP-9(matrix-metalloprotienase 9) inhibitors. Preferred anti-angiogenesisagents include sunitinib (Sutent®), bevacizumab (Avastin®), axitinib (AG13736), SU 14813 (Pfizer), and AG 13958 (Pfizer).

Additional anti-angiogenesis agents include vatalanib (CGP 79787),Sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib(Zactima®), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171(AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE 941),tetrathiomolybdata (Coprexa®), AMG 706 (Amgen), VEGF Trap (AVE 0005),CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352),and CP-868,596 (Pfizer).

Other anti-angiogenesis agents include enzastaurin (LY 317615),midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex®) andUCN 01 (Kyowa Hakko).

Other examples of anti-angiogenesis agents which can be used inconjunction with a compound of Disclosed herein and pharmaceuticalcompositions described herein include celecoxib (Celebrex®), parecoxib(Dynastat®), deracoxib (SC 59046), lumiracoxib (Preige®), valdecoxib(Bextra®), rofecoxib (Vioxx®), iguratimod (Careram®), IP 751 (Invedus),SC-58125 (Pharmacia) and etoricoxib (Arcoxia®).

Other anti-angiogenesis agents include exisulind (Aptosyn®), salsalate(Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen(Orudis®) nabumetone (Relafen®), piroxicam (Feldene®), naproxen (Aleve®,Naprosyn®) diclofenac (Voltaren®), indomethacin (Indocin®), sulindac(Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketorolac(Toradol®), and oxaprozin (Daypro®).

Other anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI005), AZD 8955 (AstraZeneca), incyclinide (Metastat®), and PCK 3145(Procyon).

Other anti-angiogenesis agents include acitretin (Neotigason®),plitidepsin (Aplidine®), cilengtide (EMD 121974), combretastatin A4(CA4P), fenretinide (4 HPR), halofuginone (Tempostatin®), Panzem®(2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291),catumaxomab (Removab®), lenalidomide (Revlimid®) squalamine (EVIZON®),thalidomide (Thalomid®), Ukrain® (NSC 631570), Vitaxin® (MEDI 522), andzoledronic acid (Zometa®)

In some embodiments, the anti-cancer agent is a so called signaltransduction inhibitor (e.g., inhibiting the means by which regulatorymolecules that govern the fundamental processes of cell growth,differentiation, and survival communicated within the cell). Signaltransduction inhibitors include small molecules, antibodies, andantisense molecules. Signal transduction inhibitors include for examplekinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threoninekinase inhibitors) and cell cycle inhibitors. More specifically signaltransduction inhibitors include, for example, ALK inhibitors, ROS1inhibitors, TrkA inhibitors, TrkB inhibitors, TrkC inhibitors, farnesylprotein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2,pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors,K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STATinhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6kinase inhibitors, inhibitors of the WNT pathway and so calledmulti-targeted kinase inhibitors.

Preferred signal transduction inhibitors include gefitinib (Iressa®),cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®),sunitinib (Sutent®) imatinib (Gleevec®), and PD325901 (Pfizer).

Additional examples of signal transduction inhibitors which may be usedin conjunction with a compound of Disclosed herein and pharmaceuticalcompositions described herein include BMS 214662 (Bristol-Myers Squibb),lonafarnib (Sarasar®), pelitrexol (AG 2037), matuzumab (EMD 7200),nimotuzumab (TheraCIM h-R3®), panitumumab (Vectibix®), Vandetanib(Zactima®), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BMW2992 (Boehringer Ingelheim), and Cervene® (TP 38).

Other examples of signal transduction inhibitor include PF-2341066(Pfizer), PF-299804 (Pfizer), canertinib (CI 1033), pertuzumab(Omnitarg®), Lapatinib (Tycerb®), pelitinib (EKB 569), miltefosine(Miltefosin®), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T(Neuvenge®), NeuVax® (E75 cancer vaccine), Osidem® (IDM 1), mubritinib(TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix®), lapatinib(Tycerb®), PF-299804 (Pfizer), pelitinib (EKB 569), and pertuzumab(Omnitarg®).

Other examples of signal transduction inhibitors include ARRY 142886(Array Biopharm), everolimus (Certican®), zotarolimus (Endeavor®),temsirolimus (Torisel®), AP 23573 (ARIAD), and VX 680 (Vertex).

Additionally, other signal transduction inhibitors include XL 647(Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), andGI-4000 (GlobeImmune).

Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib(flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam(E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032(Bristol-Myers Squibb), PD 0332991 (Pfizer), AG 024322 (Pfizer),LOXO-101 (Loxo Oncology), crizotinib, and ceritinib.

In some embodiments, the compounds of disclosed herein are used togetherwith classical antineoplastic agents. Classical antineoplastic agentsinclude but are not limited to hormonal modulators such as hormonal,anti-hormonal, androgen agonist, androgen antagonist and anti-estrogentherapeutic agents, histone deacetylase (HDAC) inhibitors, genesilencing agents or gene activating agents, ribonucleases, proteosomics,Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase IIinhibitors, alkylating agents, antimetabolites, poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor, microtubulin inhibitors, antibiotics,plant derived spindle inhibitors, platinum-coordinated compounds, genetherapeutic agents, antisense oligonucleotides, vascular targetingagents (VTAs), and statins.

Examples of classical antineoplastic agents used in combination therapywith a compound of disclosed herein, optionally with one or more otheragents include, but are not limited to, glucocorticoids, such asdexamethasone, prednisone, prednisolone, methylprednisolone,hydrocortisone, and progestins such as medroxyprogesterone, megestrolacetate (Megace), mifepristone (RU-486), Selective Estrogen ReceptorModulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene,afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene,ospemifene, tesmilifene, toremifene, trilostane and CHF 4227 (Cheisi)),Selective Estrogen-Receptor Downregulators (SERD's; such asfulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane,fadrozole, letrozole (Femara), gonadotropin-releasing hormone (GnRH;also commonly referred to as luteinizing hormone-releasing hormone[LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex),leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis),bicalutamide (Casodex), cyproterone, flutamide (Eulexin), megestrol,nilutamide (Nilandron), and osaterone, dutasteride, epristeride,finasteride, Serenoa repens, PHL 00801, abarelix, goserelin,leuprorelin, triptorelin, bicalutamide, tamoxifen, exemestane,anastrozole, fadrozole, formestane, letrozole, and combinations thereof.

Other examples of classical antineoplastic agents used in combinationwith compounds of disclosed herein include but are not limited tosuberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals),depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethylbutyrate and PXD-101; Onconase (ranpirnase), PS-341 (MLN-341), Velcade(bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche),camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan,10-hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan,Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin,10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38,edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin,annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin,etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin,novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine,rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard(dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473,altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan,carboquone, carmustine, chlorambucil, dacarbazine, estramustine,fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide,mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C,mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, andplatinum-coordinated alkylating compounds such as cisplatin, Paraplatin(carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin(oxaliplatin, Sanofi), streptozocin, satrplatin, and combinationsthereof.

In some embodiments, the compounds of disclosed herein are used togetherwith dihydrofolate reductase inhibitors (such as methotrexate andNeuTrexin (trimetresate glucuronate)), purine antagonists (such as6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine,clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed),pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta(premetrexed disodium, LY231514, MTA), capecitabine (Xeloda®), cytosinearabinoside, Gemzar® (gemcitabine, Eli Lilly), Tegafur (UFT Orzel orUforal and including TS-1 combination of tegafur, gimestat and otostat),doxifluridine, carmofur, cytarabine (including ocfosfate, phosphatestearate, sustained release and liposomal forms), enocitabine,5-azacitidine (Vidaza), decitabine, and ethynylcytidine) and otherantimetabolites such as eflornithine, hydroxyurea, leucovorin,nolatrexed (Thymitaq), triapine, trimetrexate,N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001(Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180(Guilford Pharm Inc) and combinations thereof.

Other examples of classical antineoplastic cytotoxic agents used incombination therapy with a compound of disclosed herein, optionally withone or more other agents include, but are not limited to, Abraxane(Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis),Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin,mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine,vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), Ortataxel,paclitaxel (including Taxoprexin a DHA/paciltaxel conjugate), cisplatin,carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar,capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin,Canfosfamide (Telcyta®), DMXAA (Antisoma), ibandronic acid,L-asparaginase, pegaspargase (Oncaspar®), Efaproxiral(Efaproxyn®—radiation therapy)), bexarotene (Targretin®), Tesmilifene(DPPE—enhances efficacy of cytotoxics)), Theratope® (Biomira), Tretinoin(Vesanoid®), tirapazamine (Trizaone®), motexafin gadolinium (Xcytrin®)Cotara® (mAb), and NBI-3001 (Protox Therapeutics),polyglutamate-paclitaxel (Xyotax®) and combinations thereof.

Further examples of classical antineoplastic agents used in combinationtherapy with a compound of disclosed herein, optionally with one or moreother agents include, but are not limited to, as Advexin (ING 201),TNFerade (GeneVec, a compound which express TNFalpha in response toradiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen,Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126,TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol,Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin(Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin(Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin(Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, andcombinations thereof.

Some embodiments relate to a method for the treatment of breast cancerin a human in need of such treatment, comprising administering to saidhuman an amount of a compound of disclosed herein, in combination withone or more (preferably one to three) anti-cancer agents selected fromthe group consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel,capecitabine, gemcitabine, vinorelbine, exemestane, letrozole andanastrozole.

Some embodiments provide a method of treating colorectal cancer in amammal, such as a human, in need of such treatment, by administering anamount of a compound of disclosed herein, in combination with one ormore (preferably one to three) anti-cancer agents. Examples ofparticular anti-cancer agents include those typically used in adjuvantchemotherapy, such as FOLFOX, a combination of 5-fluorouracil (5-FU) orcapecitabine (Xeloda), leucovorin and oxaliplatin (Eloxatin). Furtherexamples of particular anti-cancer agents include those typically usedin chemotherapy for metastatic disease, such as FOLFOX or FOLFOX incombination with bevacizumab (Avastin); and FOLFIRI, a combination of5-FU or capecitabine, leucovorin and irinotecan (Camptosar). Furtherexamples include 17-DMAG, ABX-EFR, AMG-706, AMT-2003, ANX-510(CoFactor), aplidine (plitidepsin, Aplidin), Aroplatin, axitinib(AG-13736), AZD-0530, AZD-2171, bacillus Calmette-Guerin (BCG),bevacizumab (Avastin), BIO-117, BIO-145, BMS-184476, BMS-275183,BMS-528664, bortezomib (Velcade), C-1311 (Symadex), cantuzumabmertansine, capecitabine (Xeloda), cetuximab (Erbitux), clofarabine(Clofarex), CMD-193, combretastatin, Cotara, CT-2106, CV-247, decitabine(Dacogen), E-7070, E-7820, edotecarin, EMD-273066, enzastaurin(LY-317615) epothilone B (EPO-906), erlotinib (Tarceva), flavopyridol,GCAN-101, gefitinib (Iressa), huA33, huC242-DM4, imatinib (Gleevec),indisulam, ING-1, irinotecan (CPT-11, Camptosar) ISIS 2503, ixabepilone,lapatinib (Tykerb), mapatumumab (HGS-ETR1), MBT-0206, MEDI-522(Abregrin), Mitomycin, MK-0457 (VX-680), MLN-8054, NB-1011, NGR-TNF,NV-1020, oblimersen (Genasense, G3139), OncoVex, ONYX 015 (CI-1042),oxaliplatin (Eloxatin), panitumumab (ABX-EGF, Vectibix), pelitinib(EKB-569), pemetrexed (Alimta), PD-325901, PF-0337210, PF-2341066,RAD-001 (Everolimus), RAV-12, Resveratrol, Rexin-G, S-1 (TS-1),seliciclib, SN-38 liposome, Sodium stibogluconate (SSG), sorafenib(Nexavar), SU-14813, sunitinib (Sutent), temsirolimus (CCI 779),tetrathiomolybdate, thalomide, TLK-286 (Telcyta), topotecan (Hycamtin),trabectedin (Yondelis), vatalanib (PTK-787), vorinostat (SAHA, Zolinza),WX-UK1, and ZYC300, wherein the amounts of the active agent togetherwith the amounts of the combination anticancer agents are effective intreating colorectal cancer.

Some embodiments provide methods for the treatment of renal cellcarcinoma in a human in need of such treatment, comprising administeringto said human an amount of a compound of disclosed herein, incombination with one or more (preferably one to three) anti-canceragents selected from the group consisting of capecitabine (Xeloda),interferon alpha, interleukin-2, bevacizumab (Avastin), gemcitabine(Gemzar), thalidomide, cetuximab (Erbitux), vatalanib (PTK-787), Sutent,AG-13736, SU-11248, Tarceva, Iressa, Lapatinib and Gleevec, wherein theamounts of the active agent together with the amounts of the combinationanticancer agents is effective in treating renal cell carcinoma.

Some embodiments provide methods for the treatment of melanoma in ahuman in need of such treatment, comprising administering to said humanan amount of a compound of disclosed herein, in combination with one ormore (preferably one to three) anti-cancer agents selected from thegroup consisting of interferon alpha, interleukin-2, temozolomide(Temodar), docetaxel (Taxotere), paclitaxel, Dacarbazine (DTIC),carmustine (also known as BCNU), Cisplatin, vinblastine, tamoxifen,PD-325,901, Axitinib, bevacizumab (Avastin), thalidomide, sorafanib,vatalanib (PTK-787), Sutent, CpG-7909, AG-13736, Iressa, Lapatinib andGleevec, wherein the amounts of the active agent together with theamounts of the combination anticancer agents is effective in treatingmelanoma.

Some embodiments provide methods for the treatment of lung cancer in ahuman in need of such treatment, comprising administering to said humanan amount of a compound disclosed herein, in combination with one ormore (preferably one to three) anti-cancer agents selected from thegroup consisting of capecitabine (Xeloda), bevacizumab (Avastin),gemcitabine (Gemzar), docetaxel (Taxotere), paclitaxel, premetrexeddisodium (Alimta), Tarceva, Iressa, Vinorelbine, Irinotecan, Etoposide,Vinblastine, and Paraplatin (carboplatin), wherein the amounts of theactive agent together with the amounts of the combination anticanceragents is effective in treating lung cancer.

DETAILED DESCRIPTION

Methods for treating, ameliorating the symptoms of, delaying theprogression of, delaying the onset of or otherwise addressing diseasescaused by and/or associated with deregulated protein kinase activity,particularly ROS family, PLK family, protein kinase C in differentisoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2,Bub-1, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3,JAK2, IGF-R, ALK, PI3K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2,IKK-2, Cdc7, Nek, Cdk/cyclin kinase family, more particularly Aurora 2,IGF-1R and ALK activity, and ROS1 activity, and further moreparticularly ALK activity and/or ROS1 activity, which comprisesadministering to a mammal in need thereof an effective amount of asubstituted indazole compound represented by formula (I) or formula2.(I) as defined below, are disclosed herein.

Some embodiments provide methods for treating a disease caused by and/orassociated with dysregulated protein kinase activity selected from thegroup consisting of cancer and cell proliferative disorders.

Some embodiments provide methods for treating specific types of cancerincluding carcinoma, squamous cell carcinoma, hematopoietic tumors ofmyeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of thecentral and peripheral nervous system, melanoma, seminoma,teratocarcinoma, osteosarcoma, xeroderma pigmentosum, angiosarcoma,glioblastoma, holangiocarcinoma, inflammatory myofibroblastic tumor,epitheloid hemangioendothelioma, astrocytoma, meningioma, angiosarcoma,epitheloid hemangiothelioma, keratocanthomas, thyroid follicular cancer,Kaposi's sarcoma, and Pancreatic cancer.

Some embodiments provide methods for treating specific types of cancersuch as, but not restricted to, breast cancer, lung cancer, colorectalcancer, prostate cancer, ovarian cancer, endometrial cancer, gastriccancer, clear cell renal cell carcinoma, invasive ductal carcinoma(breast), uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing'ssarcoma, Kaposi's sarcoma, Pancreatic cancer, and medulloblastoma.

Some embodiments provide methods for treating ALK+ Anaplastic Large CellLymphomas (ALCL) and possibly other indications in which the ALKactivity might play a role, like Neuroblastoma, Rhabdomyosarcoma,Glioblastoma, Inflammatory Myofibroblastic Tumor, and some kind ofMelanomas, Breast Carcinomas, Ewings sarcomas, Retinoblastomas and NonSmall Cell Lung Carcinomas (NSCLC).

Some embodiments provide methods for treating, reducing the symptoms of,ameliorating the symptoms of, delaying the onset of, or otherwisepharmaceutically addressing Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule of Formula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

Some embodiments provide methods for treating, reducing the symptoms of,ameliorating the symptoms of, delaying the onset of, or otherwisepharmaceutically addressing Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule of U.S. Pat. No. 8,299,057, issued Oct. 30,2012, the entirety of which is hereby incorporated by reference. Someembodiments provide methods for treating, reducing the symptoms of,ameliorating the symptoms of, delaying the onset of, or otherwisepharmaceutically addressing Pancreatic cancer and possibly otherindications in which a defect in the modulation of ROS1 activity, orupregulation, misregulation or deletion thereof might play a role byadministering a molecule of U.S. Pat. No. 8,114,865, issued Feb. 14,2012, the entirety of which is hereby incorporated by reference.

Some embodiments provide methods for treating, reducing the symptoms of,ameliorating the symptoms of, delaying the onset of, or otherwisepharmaceutically addressing Pancreatic cancer associated with a ROS1down-regulation defect, for example a null mutation such as a ROS1deletion by identifying a ROS1 down-regulation defect, for example anull mutation such as a ROS1 deletion in a cancer or precancerouspancreatic cell in an individual, and administering to the individual amolecule of Formula (I) as disclosed herein, such asN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide orN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

Some embodiments provide for identifying a ROS1 modulation defect suchas an upregulation defect or a down-regulation defect, for example anull mutation such as a ROS1 deletion or a ROS1 chimeric locus encodinga constitutively active ROS1 kinase in a cancer or precancerouspancreatic cell in an individual comprises assaying for ROS1 activity ina cell extract from a pancreatic cancerous or precancerous cellpopulation. In some embodiments identifying a ROS1 modulation defectsuch as an upregulation defect or a down-regulation defect, for examplea null mutation such as a ROS1 deletion or a ROS1 chimeric locusencoding a constitutively active ROS1 kinase in a cancer or precancerouspancreatic cell in an individual comprises assaying for ROS1 transcriptaccumulation in an RNA population from a pancreatic cancerous orprecancerous cell population. In some embodiments identifying a ROS1modulation defect such as an upregulation defect or a down-regulationdefect, for example a null mutation such as a ROS1 deletion or a ROS1chimeric locus encoding a constitutively active ROS1 kinase in a canceror precancerous pancreatic cell in an individual comprises determiningthe nucleic acid sequence such as the genomic deoxyribonucleic acidsequence in a cell or cells or a cell population comprising a cell orcells from a pancreatic cancerous or precancerous cell population.

Some embodiments provide methods to treat cell proliferative disorderssuch as, but not restricted to, benign prostate hyperplasia, familialadenomatosis polyposis, neuro-fibromatosis, psoriasis, atherosclerosisand conditions involving vascular smooth muscle proliferation orneointimal formation such as restenosis following angioplasty orsurgery, pulmonary fibrosis, arthritis, glomerulonephritis,retinopathies including diabetic and neonatal retinopathies and agerelated macular degeneration, graft vessel disease, such as can occurfollowing vessel or organ transplantation, acromegaly and disorderssecondary to acromegaly as well as other hypertrophic conditions inwhich IGF/IGF-1R signaling is implicated, such as fibrotic lung disease,pathologies related to chronic or acute oxidative stress or hyperoxiainduced tissue damage, and metabolic disorders in which elevated IGFlevels or IGF-1R activity are implicated, such as obesity.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition.

Some embodiments further comprise subjecting the mammal in need thereofto a radiation therapy or chemotherapy regimen in combination with atleast one cytostatic or cytotoxic agent. Moreover the invention providesa method for inhibiting the activity ALK protein which comprisescontacting the said protein with an effective amount of a compound offormula (I) or formula 2.(I).

Formula I

The compounds of formula (I) may have one or more asymmetric centers,and may therefore exist as individual optical isomers or racemicmixtures. Accordingly, all the possible isomers, and their mixtures, ofthe compounds of formula (I) are within the scope of the presentinvention.

Derivatives of compounds of formula (I) originating from metabolism in amammal, and the pharmaceutically acceptable bio-precursors (otherwisereferred to as pro-drugs) of the compounds of formula (I) are alsowithin the scope of the present invention.

In addition to the above, as known to those skilled in the art, theunsubstituted nitrogen on the pyrazole ring of the compounds of formula(I) rapidly equilibrates in solution to form a mixture of tautomers, asdepicted below:

X, Ar, R, R1, R2 and R3 are as defined above.

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula (I), the other tautomer (Ia) isalso within the scope of the present invention, unless specificallynoted otherwise.

The general terms as used herein, unless otherwise specified, have themeaning reported below as applied to formula (I).

The term “straight or branched C1-C6 alkyl” refers to a saturatedaliphatic hydrocarbon radical, including straight chain and branchedchain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl,2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. The alkylgroup may be substituted or unsubstituted. When substituted, thesubstituent groups are preferably one to three, independently selectedfrom the group consisting of halogen, C2-C6 alkenyl, C2-C6 alkynyl,cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10,NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, an optionallyfurther substituted C3-C6 cycloalkyl, heterocyclyl and aryl, wherein R4,R5, R6, R7, R8, R9 and R10 are as defined above.

The term “C3-C6 cycloalkyl” refers to a 3- to 6-membered all-carbonmonocyclic ring, which may contain one or more double bonds but does nothave a completely conjugated π-electron system. Examples of cycloalkylgroups, without limitation, are cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent groups are preferably one or two substituents,independently selected from the group consisting of halogen, C2-C6alkenyl, C2-C6 alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7,SR7, SOR10, SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6alkyl, an optionally further substituted straight or branched C1-C6alkyl, C3-C6 cycloalkyl, heterocyclyl and aryl, wherein R4, R5, R6, R7,R8, R9 and R10 are as defined above.

The term “heterocyclyl” refers to a 3- to 7-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms such as nitrogen, oxygen and sulfur. Notlimiting examples of heterocyclyl groups are, for instance, oxiranyl,aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, pyrazolinyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl,thiazolinyl, isothiazolinyl, dioxanyl, piperazinyl, morpholinyl,thiomorpholinyl, examethyleneiminyl, homopiperazinyl and the like. Aheterocyclyl group may be substituted or unsubstituted. Whensubstituted, the substituent groups are preferably one or twosubstituents, independently selected from the group consisting ofhalogen, C2-C6 alkenyl, C2-C6 alkynyl, cyano, nitro, NHCOR4, COR4,NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6alkyl, R8O—C1-C6 alkyl, an optionally further substituted straight orbranched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl and aryl, whereinR4, R5, R6, R7, R8, R9 and R10 are as defined above.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic hydrocarbonwith from 1 to 4 ring systems, optionally further fused or linked toeach other by single bonds, wherein at least one of the carbocyclicrings is “aromatic”, wherein the term “aromatic” refers to completelyconjugated pi-electron bond system. Non limiting examples of such arylgroups are phenyl, α- or β-naphthyl or biphenyl groups.

The term “heteroaryl” refers to aromatic heterocyclic rings, typically5- to 7-membered heterocycles with from 1 to 3 heteroatoms selectedamong N, O or S; the heteroaryl ring can be optionally further fused orlinked to aromatic and non-aromatic carbocyclic and heterocyclic rings.Not limiting examples of such heteroaryl groups are, for instance,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl,thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl,oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl,1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl,2,3-dihydroquinoxalinyl and the like.

The aryl and heteroaryl groups can be optionally substituted by one ormore, preferably one, two or three substituents independently selectedfrom halogen, C2-C6 alkenyl, C2-C6 alkynyl, cyano, nitro, NHCOR4, COR4,NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6alkyl, R8O—C1-C6 alkyl, an optionally further substituted straight orbranched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl and aryl, whereinR4, R5, R6, R7, R8, R9 and R10 are as defined above.

The term “halogen” indicates fluorine, chlorine, bromine or iodine.

The term “C2-C6 alkenyl” indicates an aliphatic C2-C6 hydrocarbon chaincontaining at least one carbon-carbon double bond and which can bestraight or branched.

Representative examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1- or 2-butenyl, and the like.

The term “C2-C6 alkynyl” indicates an aliphatic C2-C6 hydrocarbon chaincontaining at least one carbon-carbon double bond and which can bestraight or branched.

Representative examples include, but are not limited to, ethynyl,1-propynyl, 2-propynyl, 1- or 2-butynyl, and the like.

The term “cyano” indicates a —CN residue.

The term “nitro” indicates a —NO2 group.

The term “pharmaceutically acceptable salt” of compounds of formula (I)refers to those salts that retain the biological effectiveness andproperties of the parent compound.

Such salts include acid addition salts with inorganic acids such ashydrochloric, hydrobromic, nitric, phosphoric, sulfuric, perchloric acidand the like, or with organic acids such as acetic, trifluoroacetic,propionic, glycolic, lactic, (D) or (L) malic, maleic, methanesulfonic,ethanesulfonic, benzoic, p-toluenesulfonic, salicylic, cinnamic,mandelic, tartaric, citric, succinic, malonic acid and the like; saltsformed when an acidic proton present in a compound of formula (I) iseither replaced by a metal ion, e.g., an alkali metal ion such as sodiumor potassium, or an alkaline earth ion such as calcium or magnesium, orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, and the like.

Compounds of formula (I) wherein X is —CH2-, are represented by thegeneral formula (IA):

Compounds of formula (I) wherein X is —CH(OH)—, are represented by thegeneral formula (IB):

Compounds of formula (I) wherein X is —CH(OR′)—, are represented by thegeneral formula (IC):

Compounds of formula (I) wherein X is —C(R′R″)—, are represented by thegeneral formula (ID):

In some embodiments, the class of compounds of formula (I) are thecompounds wherein: X is —CH2-, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, whereinR′ is C1-C3 alkyl and R″ is hydrogen or C1-C3 alkyl; R is an optionallysubstituted C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl, and R1,R2 and R3 are independently hydrogen, halogen or hydroxy.

In some embodiments, the class of compounds of formula (I) are thecompounds wherein: X is —CH2-, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, whereinR′ is methyl and R″ is hydrogen or methyl, and R1, R2 and R3 arehydrogen.

In some embodiments, the class of compounds of formula (I) are thecompounds wherein R is an optionally substituted aryl or heteroaryl.

In some embodiments, the class of compounds of formula (I) are thecompounds wherein Ar is a group of formula:

Ra, Rb and Rc are independently hydrogen, halogen, C2-C6 alkenyl, C2-C6alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10,SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, anoptionally further substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein R4, R5, R6, R7,R8, R9 and R10 are as defined above and R is an optionally substitutedaryl.

In some embodiments, the class of compounds of formula (I) are thecompounds wherein: Ar is a group of formula:

Ra and Rb are as defined above.

In some embodiments, the class of compounds of formula (I) are thecompounds wherein: ●Ar is a group of formula:

Ra is hydrogen, halogen, nitro, NHCOR4 or NR5R6 and Rb is hydrogen,nitro, NR5R6, OR7 or R8R9N—C1-C6 alkyl wherein R4, R5, R6, R7, R8 and R9are as defined above.

Specific compounds (cpd.) of the invention are listed below:

●1. N-(5-benzyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide;

●2.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●3.N-[5-(2,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)benzamide;

●4.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)benzamide;

●5.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitrobenzamide;

●6.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;

●7.2-Amino-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●8.2-Amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●9.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●10.N-[5-(2,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●11.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●12.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(1-methyl-piperidin-4-ylamino)-benzamide;

●13.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(1-methyl-piperidin-4-ylamino)-benzamide;

●14.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide:

●15.N-[5-(2,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●16.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●17.2-cyclohexylamino-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●18.2-cyclohexylamino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●19.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●20.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●21.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

●22.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

●23.2-benzylamino-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●24.2-benzylamino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

●25.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●26.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●27.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●28.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●29.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●30.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●31.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●32.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●33.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●34.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●35.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●36.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●37.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●38.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●39.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(3-fluoro-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●40.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(3-fluoro-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●41.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-phenylamino-benzamide;

●42.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-phenylamino-benzamide;

●43. 1H-pyrrole-2-carboxylic acid[2-[5-(3-fluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

●44. 1H-pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

●45. 1H-pyrrole-3-carboxylic acid[2-[5-(3-fluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

●46. 1H-pyrrole-3-carboxylic acid[2-[5-(3,5-difluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

●47.N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-methanesulfonylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

●48.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-methanesulfonylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

●49.2-fluoro-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-5-(tetrahydro-pyran-4-ylamino)-benzamide;

●50.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(tetrahydro-pyran-4-ylamino)-benzamide;

●51.2-fluoro-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-5-(2-methoxy-ethylamino)-benzamide;

●52.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(2-methoxy-ethylamino)-benzamide;

●53.4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzyl)-1H-indazol-3-yl]-2-nitro-benzamide;

●54.2-amino-4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzyl)-1H-indazol-3-yl]-benzamide;

●55.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●56.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

●57.2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide;

●58.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide;

●59.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-benzamide;

●60.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●61.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●62.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;

●63.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●64.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●65.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●66.N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●67.N-{5-[(3-ethoxy-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;

●68.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●69.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●70.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;

●71.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●72.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●73.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●74.N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●75.N-{5-[1-(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●76.N-{5-[1-(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●77.N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;

●78.N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●79.N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●80.N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●81.N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●82.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●83.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●84.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;

●85.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●86.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●87.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●88.N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●89.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●90.N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●91.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[4-(dimethylamino)piperidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●92.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●93.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-3-(4-methylpiperazin-1-yl)benzamide;

●94.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(2S)-1-methylpyrrolidin-2-yl]methoxyl-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●95.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(1-methylpiperidin-4-yl)oxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●96.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[2-(dimethylamino)ethoxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●97.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●98.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●99.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-{[cis-4-(trifluoromethyl)cyclohexyl]amino}benzamide;

●100.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]amino}benzamide;

●101.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;

●102.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide;

●103.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(cis-4-hydroxycyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzamide;

●104.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(trans-4-hydroxycyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzamide;

●105.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(2-hydroxyethyl)amino]-4-(4-methylpiperazin-1-yl)benzamide;

●106.2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide;

●107.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-{[(1-methylazetidin-3-yl)methyl]amino}-4-(4-methylpiperazin-1-yl)benzamide;

●108.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(1-methylpiperidin-4-yl)amino]-2-[tetrahydro-2H-pyran-4-ylamino]benzamide;

●109.4-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●110.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methylpiperidin-4-yl)amino]benzamide;

●111.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methylpiperidin-4-yl)amino]-4-(morpholin-4-yl)benzamide;

●112.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-methoxy-4-(4-methylpiperazin-1-yl)benzamide;

●113.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-(4-methylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide;

●114.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-6-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)pyridine-3-carboxamide;

●115.1-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)benzyl]piperidine;

●116.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●117.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(pyrrolidin-1-ylmethyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●118.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(morpholin-4-ylmethyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●119.4-(azetidin-1-ylmethyl)-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●120.N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-benzamide;

●121.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methyl}benzamide;

●122.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-(morpholin-4-ylmethyl)benzamide;

●123.N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide;

●124.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide;

●125.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide;

●126.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonyl}benzamide;

●127.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●128.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●129.N1-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N4-[2-(dimethylamino)ethyl]-N4-methyl-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide;

●130.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●131.N1-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N4-[2-(dimethylamino)ethyl]-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide;

●132.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(4-methylpiperazin-1-yl)carbonyl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●133.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●134.N1-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N4-(1-methylpiperidin-4-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide;

●135.N-[5-(2-methyl-5-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●136.4-(4-methylpiperazin-1-yl)-N-[5-(pyridin-3-ylmethyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●137.N-[5-benzyl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

●138. ethyl4-{[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate;

●139.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(piperidin-4-ylamino)benzamide;

●140. ethyl5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate;

●141.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

●142.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●143.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●144.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;

●145.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methyl}benzamide,and

●146.N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide.

In some embodiments, the compound of the invention is:N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

The synthesis of the compounds of formula (I), is described in U.S. Pat.No. 8,299,057, issued Oct. 30, 2012, which is hereby incorporated byreference in its entirety.

Formula 2.(I).

The compounds of formula 2.(I) may have one or more asymmetric centers,and may therefore exist as individual optical isomers or racemicmixtures. Accordingly, all the possible isomers, and their mixtures, ofthe compounds of formula 2.(I) are within the scope of the presentinvention.

Derivatives of compounds of formula 2.(I) originating from metabolism ina mammal, and the pharmaceutically acceptable bio-precursors (otherwisereferred to as pro-drugs) of the compounds of formula 2.(I) are alsowithin the scope of the present invention.

In addition to the above, as known to those skilled in the art, thepyrazole ring of the compounds of formula 2.(I) rapidly equilibrates insolution to form a mixture of tautomers, as depicted below:

wherein Ar, R, R1, R2 and R3 are as defined above.

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula 2.(I), the other tautomer 2.(Ia)is also within the scope of the present invention, unless specificallynoted otherwise.

The general terms as used herein, unless otherwise specified, have themeaning reported below as applied to formula 2.(I).

The term “straight or branched C1-C6 alkyl” refers to a saturatedaliphatic hydrocarbon radical, including straight chain and branchedchain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl,2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. The alkylgroup may be substituted or unsubstituted. When substituted, thesubstituent groups are preferably one to three, independently selectedfrom the group consisting of halogen, alkenyl, alkynyl, cyano, nitro,NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10, NHSOR10,NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, an optionally furthersubstituted C3-C6 cycloalkyl, heterocyclyl and aryl, wherein R4, R5, R6,R7, R8, R9 and R10 are as defined above.

The term “C3-C6 cycloalkyl” refers to a 3- to 6-membered all-carbonmonocyclic ring, which may contain one or more double bonds but does nothave a completely conjugated 7c-electron system. Examples of cycloalkylgroups, without limitation, are cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent groups are preferably one or two substituents,independently selected from the group consisting of halogen, alkenyl,alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10,SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, anoptionally further substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl and aryl, wherein R4, R5, R6, R7, R8, R9 andR10 are as defined above.

The term “heterocyclyl” refers to a 3- to 7-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms. These heteroatoms can include, but are notlimited to, nitrogen, oxygen and sulfur. Not limiting examples ofheterocyclyl groups are, for instance, oxiranyl, aziridinyl, oxetanyl,azetidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,pyrazolinyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl, thiazolinyl,isothiazolinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl,hexamethyleneiminyl, homopiperazinyl and the like. A heterocyclyl groupmay be substituted or unsubstituted. When substituted, the substituentgroups are preferably one or two substituents, independently selectedfrom the group consisting of halogen, alkenyl, alkynyl, cyano, nitro,NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10, NHSOR10, NHS2R10,R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, an optionally further substitutedstraight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl andaryl, wherein R4, R5, R6, R7, R8, R9 and R10 are as defined above.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic as well as aheterocyclic system with from 1 to 4 rings, either fused or linked toeach other by single bonds, wherein at least one of the carbocyclic orheterocyclic rings is aromatic. Not limiting examples of aryl groupsare, for instance, phenyl, α- or β-naphthyl, 9,10-dihydroanthracenyl,indanyl, fluorenyl, biphenyl, pyrrolyl, furoyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl,benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzo isothiazolyl,triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl andthe like.

The term “aryl” may also refer to aromatic carbocyclic or heterocyclicrings further fused or linked to non-aromatic heterocyclic rings,typically 5- to 7-membered heterocycles. Not limiting examples of sucharyl groups are, for instance, 2,3-dihydroindolyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, benzopyranyl,2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.

The aryl group can be optionally substituted by one or more, preferablyone, two, or three substituents independently selected from halogen,alkenyl, alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7,SOR10, SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, anoptionally further substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl and aryl, wherein R4, R5, R6, R7, R8, R9 andR10 are as defined above.

The term “halogen” indicates fluorine, chlorine, bromine or iodine.

The term “alkenyl” indicates straight or branched C2-C6 alkyl groupsbearing a double bond. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and thelike.

The term “alkynyl” indicates straight or branched C2-C6 alkyl groupsbearing a triple bond. Representative examples include, but are notlimited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and thelike.

The term “cyano” indicates a —CN residue.

The term “nitro” indicates a —NO2 group.

References herein to “compounds” are meant to encompass, alternatively,pharmaceutically acceptable salts of such compounds.

The term “pharmaceutically acceptable salt” of compounds of formula2.(I) or any other compounds referenced herein refers to those saltsthat retain the biological effectiveness and properties of the parentcompound. Such salts include:

Acid addition salts with inorganic acids such as hydrochloric,hydrobromic, nitric, phosphoric, sulfuric, perchloric acid and the like,or with organic acids such as acetic, trifluoroacetic, propionic,glycolic, lactic, (D) or (L) malic, maleic, methanesulfonic,ethanesulfonic, benzoic, p-toluenesulfonic, salicylic, cinnamic,mandelic, tartaric, citric, succinic, malonic acid and the like; saltsformed when an acidic proton present in a compound of formula 2.(I) iseither replaced by a metal ion, e.g., an alkali metal ion such as sodiumor potassium, or an alkaline earth ion such as calcium or magnesium, orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, and the like.

In some embodiments, the class of compounds of formula 2.(I) are thecompounds wherein: R is an optionally further substituted C3-C6cycloalkyl, heterocyclyl or aryl and R1, R2 and R3 are independentlyhydrogen, halogen or hydroxy.

In some embodiments, the class of compounds of formula 2.(I) are thecompounds wherein: Ar is an optionally further substituted phenyl,pyridinyl, pyrimidinyl or pyrazinyl.

In some embodiments, the compounds of formula 2.(I) are the compoundswherein: R1, R2 and R3 are hydrogen.

In some embodiments, the class of compounds of formula 2.(I) are thecompounds wherein: Ar is an optionally further substituted phenyl orpyridinyl and R is an optionally further substituted aryl.

In some embodiments, the class of compounds of formula 2.(I) are thecompounds wherein:

Ar is a group of formula:

wherein Ra, Rb and Rc are independently hydrogen, halogen, alkenyl,alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10,SO2R10, NHSOR10, NHSO2R10, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, anoptionally further substituted straight or branched C1-C6 alkyl, C3-C6cycloalkyl, heterocyclyl or aryl, wherein R4, R5, R6, R7, R8, R9 and R10are as defined above and R is an optionally further substituted aryl.

In some embodiments, the class of compounds of formula 2.(I) are thecompounds wherein: Ar is a group of formula:

Ra and Rb are as defined above and R is an optionally furthersubstituted aryl.

In some embodiments, the class of compounds of formula 2.(I) are thecompounds wherein: Ar is a group of formula:

Ra is hydrogen, halogen, nitro, NHCOR4 or NR5R6 and Rb is hydrogen,nitro, NR5R6, OR7 or R8R9N—C1-C6 alkyl wherein R4, R5, R6, R7, R8 and R9are as defined above and R is an optionally further substituted phenyl.

Some compounds (cpd.) of the invention are listed below:

1.N-(5-Benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide;

2.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

3.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

4.N-(5-Benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;

5.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;

6.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;

7.2-Amino-N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide;

8.2-Amino-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

9.2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

10.N-(5-Benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

11.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

12.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

13.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

14.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

15.2-Cyclohexylamino-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

16.2-Cyclohexylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

17.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

18.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

19.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(pyrrolidin-2-ylmethyl)-amino]-benzamide;

20.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(pyrrolidin-2-ylmethyl)-amino]-benzamide;

21.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(piperidin-3-ylmethyl)-amino]-benzamide;

22.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(piperidin-3-ylmethyl)-amino]-benzamide;

23.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(1-methyl-pyrrolidin-2-ylmethyl)-amino]-benzamide;

24.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(1-methyl-pyrrolidin-2-ylmethyl)-amino]-benzamide;

25.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-4-ylamino)-benzamide;

26.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-4-ylamino)-benzamide;

27.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-3-ylamino)-benzamide;

28.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-3-ylamino)-benzamide;

29.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide;

30.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide;

31.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-[(furan-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide;

32.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-[(furan-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide;

33. 1H-Pyrrole-2-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

34. 1H-Pyrrole-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

35. 1H-Pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

36. (S)-Tetrahydro-furan-2-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

37. (S)-Tetrahydro-furan-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

38. (S)-Tetrahydro-furan-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

39. 1H-Pyrrole-3-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

40. 1H-Pyrrole-3-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

41. 1H-Pyrrole-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

42.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-isobutyrylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

43.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-isobutyrylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

44. 2-(Cyclobutanecarbonyl-amino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

45.2-(Cyclobutanecarbonyl-amino)-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

46.2-(2-Amino-acetylamino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

47.2-(2-Amino-acetylamino)-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

48.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methylamino-acetylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

49.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methylamino-acetylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

50.2-(2-Dimethylamino-acetylamino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

51.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-dimethylamino-acetylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

52.2-((S)-2-Amino-propionylamino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

53.2-((S)-2-Amino-propionylamino)-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

54. (S)-Pyrrolidine-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

55. (S)-Pyrrolidine-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

56. Piperidine-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

57. Piperidine-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

58. Piperidine-3-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

59. Piperidine-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

60. Piperidine-4-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

61. Piperidine-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

62. (R)-Tetrahydro-furan-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

63. Tetrahydro-furan-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

64. Tetrahydro-pyran-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

65. Pyridine-2-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

66. Pyridine-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

67. Pyridine-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

68. 3H-Imidazole-4-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

69. 3H-Imidazole-4-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

70. 3H-Imidazole-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

71. 1-Methyl-1H-pyrrole-2-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

72. 1-Methyl-1H-pyrrole-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

73. 1-Methyl-1H-pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

74. Furan-2-carboxylic acid[2-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

75. Furan-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

76. 5-Methyl-isoxazole-4-carboxylic acid[2-(5-benzenesulfonyl-1H-indazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

77. 5-Methyl-isoxazole-4-carboxylic acid[2-[5(3-fluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

78. 5-Methyl-isoxazole-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;

79.N-(5-Benzenesulfonyl-1H-indazol-3-yl)-2-benzoylamino-4-(4-methyl-piperazin-1-yl)-benzamide;

80.2-Benzoylamino-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

81.2-Benzoylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;

82.N-[5-(3-Chloro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

83.N-[5-(3-Methoxy-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

84.N-[5-(3,5-Dichloro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

85.N-[5-(3-Fluoro-5-methoxy-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

86.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

87.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

88.4-Fluoro-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

89.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-fluoro-2-(tetrahydro-pyran-4-ylamino)-benzamide;

90.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-methoxy-2-(tetrahydro-pyran-4-ylamino)-benzamide;

91.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-methoxy-2-(tetrahydro-pyran-4-ylamino)-benzamide;

92.4-Dimethylamino-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

93.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide;

94.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

95.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

96.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-piperazin-1-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

97.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-piperazin-1-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

98.4-(4-Ethyl-piperazin-1-yl)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

99.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-ethyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

100.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-propyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

101.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-propyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

102.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-isopropyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

103.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-isopropyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

104.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-[1,4]diazepan-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

105.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-[1,4]diazepan-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

106.4-(4-Ethyl-[1,4]diazepan-1-yl)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

107.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-ethyl-[1,4]diazepan-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

108.4-(2-Dimethylamino-ethoxy)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

109.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-dimethylamino-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

110.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-pyrrolidin-1-yl-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

111.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-pyrrolidin-1-yl-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

112.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

113.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

114.4-Dimethylaminomethyl-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

115.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-dimethylaminomethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

116.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-pyrrolidin-1-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

117.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-pyrrolidin-1-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

118.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-piperidin-1-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

119.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-piperidin-1-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

120.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-morpholin-4-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

121.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-morpholin-4-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-benzamide;

122.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

123.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

124.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2,4-bis-(tetrahydro-pyran-4-ylamino)-benzamide;

125.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2,4-bis-(tetrahydro-pyran-4-ylamino)-benzamide;

126.4-(2-Dimethylamino-1-methyl-ethylamino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

127.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-dimethylamino-1-methyl-ethylamino)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

128.4-(2-Diethylamino-1-methyl-ethylamino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

129.4-(2-Diethylamino-1-methyl-ethylamino)-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

130.4-(2-Dimethylamino-ethylamino)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

131.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-dimethylamino-ethylamino)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

132.4-[(2-Dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

133.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

134.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-{[2-(isopropyl-methyl-amino)-ethyl]-methyl-amino}-2-(tetrahydro-pyran-4-ylamino)-benzamide;

135.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-{[2-(isopropyl-methyl-amino)-ethyl]-methyl-amino}-2-(tetrahydro-pyran-4-ylamino)-benzamide;

136.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

137.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

138.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

139.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

140.4-[(2-Dimethylamino-ethyl)-ethyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

141.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-ethyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

142.4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

143.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

144.4-(4-Dimethylamino-piperidin-1-yl)-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

145.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-dimethylamino-piperidin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

146.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

147.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;

148.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

149.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;

150.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

151.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

152.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(2-methoxy-ethylamino)-benzamide;

153.4-[(2-Dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-benzamide;

154.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2-methoxy-ethylamino)-benzamide;

155.4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-benzamide;

156.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-1-methyl-ethyl)-methyl-amino]-2-(2-methoxy-ethylamino)-benzamide;

157.4-[(2-Dimethylamino-1-methyl-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-benzamide;

158.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

159.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

160.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

161.4-[(2-Dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

162.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

163.4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

164.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-1-methyl-ethyl)-methyl-amino]-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

165.4-[(2-Dimethylamino-1-methyl-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

166.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-dimethylaminomethyl-2-(2-methoxy-1-methyl-ethylamino)-benzamide;

167.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

168.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

169.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-((S)-2-methoxy-1-methyl-ethylamino)-benzamide;

170.4-[(2-Dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-benzamide;

171.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-((S)-2-methoxy-1-methyl-ethylamino)-benzamide;

172.4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-benzamide;

173.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-1-methyl-ethyl)-methyl-amino]-2-((S)-2-methoxy-1-methyl-ethylamino)-benzamide;

174.4-[(2-Dimethylamino-1-methyl-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-benzamide;

175.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

176.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

177.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide;

178.4-[(2-Dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide;

179.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide;

180.4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide;

181.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-1-methyl-ethyl)-methyl-amino]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide;

182.4-[(2-Dimethylamino-1-methyl-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-benzamide;

183.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

184.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

185.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

186.4-[(2-Dimethylamino-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

187.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

188.4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

189.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-1-methyl-ethyl)-methyl-amino]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

190.4-[(2-Dimethylamino-1-methyl-ethyl)-methyl-amino]-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;

191.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

192. N-[5-(35-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

193.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

194.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

195.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-1-methoxymethyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

196.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-1-methoxymethyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

197.2-Fluoro-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-6-(tetrahydro-pyran-4-ylamino)-benzamide;

198.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-fluoro-6-(tetrahydro-pyran-4-ylamino)-benzamide;

199.2-Fluoro-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-6-(tetrahydro-pyran-4-ylamino)-benzamide;

200.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-fluoro-4-(4-methyl-piperazin-1-yl)-6-(tetrahydro-pyran-4-ylamino)-benzamide;

201.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide;

202.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide;

203.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-3-(2-methoxy-1-methyl-ethylamino)-isonicotinamide;

204.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-3-(2-methoxy-1-methyl-ethylamino)-isonicotinamide;

205.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-nicotinamide;

206.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-nicotinamide;

207.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-6-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-nicotinamide;

208.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-6-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-nicotinamide;

209.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-3-[(1H-pyrrole-2-carbonyl)-amino]-isonicotinamide;

210.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-3-[(1H-pyrrole-2-carbonyl)-amino]-isonicotinamide;

211.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-[(1H-pyrrole-2-carbonyl)-amino]-nicotinamide;

212.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-[(1H-pyrrole-2-carbonyl)-amino]-nicotinamide;

213.3-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-isonicotinamide;

214.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-fluoro-2-nitro-benzamide;

215.2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-benzamide;

216.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-isobutylamino-benzamide;

217.N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-2-nitro-benzamide;

218.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-nitro-2-(tetrahydro-pyran-4-ylamino)-benzamide;

219.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-benzamide;

220.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide;

221.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide;

222. 1-Piperidin-4-yl-1H-pyrazole-4-carboxylic acid[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-amide;

223.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

224.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

225.N-(5-Benzenesulfonyl-1H-indazol-3-yl)-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

226.N-[5-(3,5-Difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-fluoro-1-fluoromethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;

227.N-[5-(3-Fluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-(2-fluoro-1-fluoromethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamideand

228.N-(5-Benzenesulfonyl-1H-indazol-3-yl)-2-(2-fluoro-1-fluoromethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide.

The present invention also provides a process for the preparation of acompound of formula 2.(I)

The synthesis of the compounds of formula 2.(I), is described in U.S.Pat. No 8,114,865, issued Feb. 14, 2012, which is hereby incorporated byreference in its entirety.

Pharmacology

The short forms and abbreviations used herein have the followingmeaning: Ci—Curie; DMSO—dimethylsulfoxide; ID—identity; KDa—kiloDalton;microCi—microCurie; Mg—milligram; Microg—microgram; mL—milliliter;microL—microliter; M—molar; mM—millimolar; microM—micromolar;nM—nanomolar.

Molecular Screening

Transcript accumulation levels, genomic locus screening methods, andprotein kinase activity assays for ROS1, ALK, TrkA, TrkB, TrkC, or orany kinase recited herein, or a combination thereof, may be performedusing methods known to one of skill in the art. Kinase assays may beperformed by providing a substrate to a protein extract comprising ROS1,ALK, TrkA, TrkB, TrkC, or any kinase recited herein. ROS1, ALK, TrkA,TrkB, TrkC, or any kinase recited herein locus sequencing may beperformed using, for example, whole genome shotgun sequencing, ortargeted sequencing of the ROS1, ALK, TrkA, TrkB, TrkC, or any kinaserecited herein locus, for example through targeted amplification of thelocus or a region spanning the locus wholly or in part, using PCRtechniques know to one of skill in the art and primers generated throughmeans known to one of skill in the art, followed by sequencing of anygenerated amplicons. Molecular alterations can be detected by nextgeneration sequencing (NGS), quantitative reverse-transcriptionpolymerase chain reaction DNA amplification reactions (qPCR),fluorescence in situ hybridization (FISH), and/or immunohistochemistry(IHC) and are inclusive of gene rearrangements, single-nucleotidepolymorphisms (SNPs), insertions, deletions, splice variants, geneamplifications, and aberrant RNA/protein expression.

Copy number variations (CNVs), point mutations (SNPs/SNVs), insertions,deletions, gene rearrangements, RNA/protein over expression, andconstitutive phosphorylation are measurable alterations that can resultin oncogenic perturbation of ROS1, ALK, TrkA, TrkB, TrkC, or any kinaserecited herein, such as misregulation, upregulation, or downregulationthrough and including downregulation to complete loss of activity. ADNA-based test can detect CNVs, SNPs, insertions, deletions, and generearrangements. An RNA-based test can detect over expression, underexpression (up to and including complete loss of expression) ormisexpression of ROS1, ALK, TrkA, TrkB, TrkC, or any kinase recitedherein mRNA and many of the alterations detected in the DNA-based test.Protein-based tests allow one to measure the over expression, underexpression (through and including complete loss of expression) ormisexpression of ROS1, ALK, TrkA, TrkB, TrkC, or any kinase recitedherein protein; constitutive phosphorylation, constitutivedephosphorylation or misphosphorylation of the ROS1, ALK, TrkA, TrkB,TrkC, or any kinase recited herein protein; and increase, decrease(through and including complete loss) or altered activity pattern ofROS1, ALK, TrkA, TrkB, TrkC, or any kinase recited herein kinaseactivity.

Preparation of formulation and dosage forms comprisingN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

Hard gelatin capsules comprising 50 mg, 100 mg, and 200 mg ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide were prepared as follows.

The required amounts of active ingredient and excipients are weighedinto the warehouse dispensing area. The weight ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide and the mannitol are adjusted according to the active desiredpotency of the dosage form. (1) Manually pre-mixN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide and colloidal silicon dioxide into a polyethylene (PE) bag.(2) The resulting mixture from step 1 is passed through a 0.500 mmscreen size sieve, along with a portion of the pregelatinized starch andmannitol and the resulting materials are collected in a blender. (3) Theresulting mixture from step 2 is further mixed for about 20 minutes at20-25 rpm. (4) The pregelatinized starch and magnesium stearate and arepre-mixed together and are passed through a 0.500 mm screen size sieve.(5) The material from step 4 are mixed together with the materials fromstep 3 and mixed for about 20 minutes at 20-25 rpm. (6) The blendresulting from step 5 is filled into hard gelatin capsules using anautomatic capsule filling machine. Representative formulations ofcapsules comprising 50 mg, 100 mg or 200 mg ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide are shown below.

50 mg capsule representative batch formulation Batch formula Amount 50mg (6,000 per capsule Components Function capsules) 50 mgN-[5-(3,5-difluorobenzyl)-1H- Active   300 g    50 mgindazol-3-yl]-4-(4-methyl- ingredient piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide Mannitol Filler 255.00 g  42.50 mgPregelatinized starch Filler 102.75 g 17.125 mg Colloidal silicondioxide Glidant  10.50 g  1.750 mg Magnesium sterate Lubricant  6.75 g 1.125 mg Total 675.00 g 112.50 mg

100 mg capsule representative batch formulation Batch formula Amount 100mg (3,600 per capsule Components Function capsules) 100 mgN-[5-(3,5-difluorobenzyl)-1H- Active  360.0 g 100.00 mgindazol-3-yl]-4-(4-methyl- ingredient piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide Mannitol Filler 306.00 g  85.00 mgPregelatinized starch Filler 123.30 g  34.25 mg Colloidal silicondioxide Glidant  12.60 g  3.50 mg Magnesium sterate Lubricant  8.10 g 2.25 mg Total 810.00 g 225.00 mg

200 mg capsule representative batch formulation Batch formula Amount 200mg (4,100 per capsule Components Function capsules) 200 mgN-[5-(3,5-difluorobenzyl)-1H- Active  820.00 g 200.00 mgindazol-3-yl]-4-(4-methyl- ingredient piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide Mannitol Filler  697.00 g 170.00 mgPregelatinized starch Filler  280.85 g  68.50 mg Colloidal silicondioxide Glidant  28.70 g  7.00 mg Magnesium sterate Lubricant  18.45 g 4.50 mg Total 1845.00 g 450.00 mg

A dose escalation study ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide was conducted in human patients with advanced solid tumors.N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide was dosed orally once/day in a 4 day on, 3 day off schedulefor 3 weeks, followed by a 7 day rest period, in continuous 28-daycycles (Schedule A); once/day in continuous 28-day cycles (Schedule B);and once/day in a 4 day on, 3 day off schedule without interruption incontinuous 28-day cycles (Schedule C). A minimum of 3 patients wereenrolled at each dose level. Endpoints include safety, PK, and tumorresponse by response evaluation criteria in solid tumors (RECIST).

Schedule A evaluated ascending oral doses ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide once daily (fasted state) in a 4-day on, 3-day off schedulefor 3 weeks, followed by a 7-day rest period, in continuous 28-daycycles. Dose escalation was conducted according to the standard ‘3+3’scheme.

Schedule B evaluated ascending oral doses ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide once daily (fed state) without rest, in continuous 28-daycycles.

Schedule C evaluated ascending oral doses ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide once daily (fed state) in a 4-day on, 3-day off schedule for 4weeks without rest, in continuous 28-day cycles.

Patients on each dosing schedule and at each dose Schedule Cohort DailyDose Level # of Patients A 1 100 mg/m² 3 2 200 mg/m² 3 3 400 mg/m² 4 4800 mg/m² 3 5 1200 mg/m²  3 6 1600 mg/m²  3 B 1 200 mg/m² 3 C 1 400mg/m² 3

Patient cancer diagnosis and associated molecular alterations Number ofPrimary Diagnosis Molecular Alteration patients NSCLC ALK rearrangementROS1 6 rearrangements  8* 1 deletion 8 1 copy number gain CRC TrkArearrangement 1 ROS1 deletion 1 Neuroblastoma ALK mutation 2 ROS1rearrangement 1 TrkA overexpression 1 Glioblastoma None** 1 PancreaticROS1 deletion 1 Leiomyosarcoma ALK deletion 1

Steady state pK profile ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in patients on dosing Schedule A

Exposure toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in patients on dosing Schedule A increased in an approximatedose proportional manner up to doses of 800 mg/m². The mean plasmahalf-life was 17-44 hours following administration. The most commonadverse events (AEs) (mainly grade 1-2) considered possiblytreatment-related included nausea, paresthesia, vomiting, diarrhea,asthenia, myalgia, arthralgia, and dysgeusia. There was one possiblytreatment-related grade 3 AE of asthenia.

Adverse Event G1 (%) G2 (%) Total (%)** Nausea 14 (56)  2 (8) 16 (64) Paresthesia 15 (60)  0 (0) 15 (60)  Asthenia 9 (36)  3 (12) 13 (52) Vomiting 7 (28) 2 (8) 9 (36) Diarrhea 6 (24) 2 (8) 8 (32) Myalgia 6 (24)1 (4) 7 (28) Abdominal pain 4 (16) 2 (8) 6 (24) Back Pain 5 (20) 1 (4) 6(24) Arthralgia 3 (12)  3 (12) 6 (24) Headache 6 (24) 0 (0) 6 (24)Dyspnea 3 (12) 1 (4) 6 (24) Pyrexia 6 (24) 0 (0) 6 (24) Dysgeusia 6 (24)0 (0) 6 (24) Cough 4 (16) 1 (4) 5 (20)

Results

Non-small cell lung cancer (NSCLC) patients (N=4).

A 46 year old female, with a ROS1 rearrangement, s/p 2 cycles ofchemotherapy, achieved complete response after 2 cycles ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (400 mg/m2/day, Schedule C). Complete response is ongoing(patient is currently in cycle 2).

A 63 year old female with metastatic adenocarcinoma, ALK rearrangement,s/p 4 cycles of chemotherapy, crizotinib, achieved partial responseafter 4 cycles ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (1200 mg/m2/day, Schedule A). Partial response is ongoing(patient is currently in cycle 10).

A 44 year old female with metastatic disease (CNS metastases), ROS1rearrangement, s/p 3 cycles of chemotherapy, erlotinib, s/p surgery/XRTto brain, achieved partial response after 2 cycles ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (1200 mg/m²/day, Schedule A). The patient exhibited a partialresponse that is ongoing (patient currently in cycle 9).

A 63 year old male, ROS1 rearrangement, s/p 3 cycles of chemotherapy,achieved partial response after 1 cycle ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (400 mg/m2/day, Schedule C). Partial response is ongoing(patient currently in cycle 3).

Colorectal Cancer (CRC) (N=1).

A 75 year old female with metastatic CRC, TrkA rearrangement, s/p 3cycles of chemotherapy, cetuximab, achieved partial response after 1cycle ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (1600 mg/m², Schedule A). Partial response lasted for 4 cyclesbefore progressive disease.

Neuroblastoma (NB) (N=1).

A 22 year old female with metastatic NB, ALK mutation, s/p 4 cycles ofchemotherapy, achieved partial response after 12 cycles ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (started at 200 mg/m²/day and had subsequent dose escalationsto1200 mg/m²/day, Schedule A). Partial response is ongoing (the patientis currently in cycle 21).

A total of 25 patients were evaluated across 3 different dosingschedules in this trial ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

There was a complete response in a patient with non-small cell lungcancer (NSCLC) with a ROS1 molecular alteration. There were 5 partialresponses (3 of these durable >9 cycles) across multiple tumor types(NSCLC, CRC and NB) in patients with TrkA, ROS1, and ALK molecularalterations; moreover, there were 2 patients with prolonged stabledisease (11+ cycles) with NSCLC and pancreatic adenocarcinoma.

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide was well tolerated in all dosing schedules tested, includingintermittent and daily continuous administration.

Most common AEs (mainly grade 1-2) considered possibly drug-related werenausea, paresthesia, vomiting, diarrhea, asthenia, myalgia, arthralgia,and dysgeusia.

Only 1 possibly drug-related Grade>3 AE was observed: asthenia (Grade 3in one patient).

No drug limiting toxicities, study discontinuations due to adverseevents, or drug-related serious adverse events were reported.

Schedule A was terminated at 1600 mg/m2/day due to a plateau ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide exposure and the data were presented previously.

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide was well tolerated in all dosing schedules tested (both on anintermittent and daily continuous basis). Most AEs≤Grade 2.

Only 1 possibly drug-related Grade>3 AE has been observed: asthenia(1200 mg/m², Schedule A), that subsided with dose reduction to 800mg/m²/day.

No DLTs, study discontinuations due to AEs, or drug-related SAEs werereported in any dosing schedule.

Exposure toN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide increased in an approximate dose proportional manner up todoses of 800 mg/m² with mean plasma half-life of 17 to 44 hours.

Responders tended to have higher exposure than non-responders throughoutthe entire dosing cycle in Schedule A.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

The term “wild-type” as used herein refers to the protein, nucleic acidsequence, allele, locus, or activity level of a protein in adisease-free cell of a healthy individual with respect to a disease inquestion. For example, a wild-type ROS1 activity level corresponds to anactivity level of ROS1 in a healthy cell of an individual lacking aROS1-related disease or pre-disease condition.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

What is claimed is:
 1. A method of treating neuroblastoma in a patient,wherein said neuroblastoma is associated with deregulated protein kinaseactivity, the method comprising administering to said patient atherapeutically effective amount of a compound selected from the groupconsisting ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.
 2. The methodof claim 1, wherein the compound isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.
 3. The methodof claim 1, wherein the compound isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.
 4. The methodof claim 1, wherein the compound isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.
 5. The methodof claim 1, wherein said neuroblastoma is associated with deregulatedprotein kinase activity of ROS1.
 6. The method of claim 1, wherein saidneuroblastoma is associated with deregulated protein kinase activity ofTrkA.
 7. The method of claim 1, wherein said neuroblastoma is associatedwith deregulated protein kinase activity of TrkB.
 8. The method of claim1, wherein said neuroblastoma is associated with deregulated proteinkinase activity of TrkC.
 9. A method of inhibiting deregulated proteinkinase activity in a neuroblastoma cell, wherein said deregulatedprotein kinase activity is one or more of tyrosine kinase ROSI, highaffinity receptor tyrosine kinase TrkA, TrkB or TrkC activity,comprising administering to said cell an effective amount of a compoundselected from the group consisting ofN-[5-(3,5-difluorobetizyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide,N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, andN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide,or a pharmaceutically acceptable salt thereof.
 10. The method of claim9, wherein the compound isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.
 11. The methodof claim 9, wherein the compound isN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide, or a pharmaceutically acceptable salt thereof.
 12. The methodof claim 9, wherein the compound isN-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)benzamide, or a pharmaceutically acceptable salt thereof.
 13. The methodof claim 9, wherein said deregulated protein kinase activity is activityof ROS1.
 14. The method of claim 9, wherein said deregulated proteinkinase activity is activity of TrkA.
 15. The method of claim 9, whereinsaid deregulated protein kinase activity is activity of TrkB.
 16. Themethod of claim 9, wherein said deregulated protein kinase activity isactivity of TrkC.